Tablets

TABLET
 Contents………..
 Tablet Introduction
 Advantages of the Tablet dosage form
 Disadvantages of Tablet dosage form
 General properties of Tablet dosage forms
 Different types of Tablets
 Tablet Ingredients
 Granulation technology on large scale by various
techniques
 Tablet Compression
 Introduction:
• Solid medicaments may be administered orally as
powders, pills, cachets, capsules or tablets .
• These dosage forms contain a quantity of drug which is
given as a single unit and they are known collectively as
solid unit dosage forms, even in the case of sustained
action preparations which, technically, contain the
equivalent of several normal doses of drug.
• Tablets and capsules, on the other hand, currently account
for well over two third of the total number and cost of
medicines produced all over the world.
 Introduction:
• Tablet is defined as a compressed solid dosage form
containing medicaments with or without excipients.
According to the Indian Pharmacopoeia,
Pharmaceutical tablets are solid, flat or biconvex dishes,
unit dosage form, prepared by compressing a drugs or a
mixture of drugs, with or without diluents.
• They vary in shape and differ greatly in size and weight,
depending on amount of medicinal substances and the
intended mode of administration.
• It is the most popular dosage form and 70% of the total
medicines are dispensed in the form of Tablet. All
medicaments are available in the Tablet form except
where it is difficult to formulate or administer.
Advantages of the Tablet dosage form:
1. They are unit dosage form and offer the greatest
capabilities of all oral dosage form for the greatest dose
precision and the least content variability.
2. Cost is lowest of all oral dosage form.
3. Lighter and compact.
4. Easiest and cheapest to package and strip.
5. Easy to swallowing with least tendency for hang-up.
6. Sustained release product is possible by enteric coating.
7. Objectionable odour and bitter taste can be masked by
coating technique.
8. Suitable for large scale production.
9. Greatest chemical and microbial stability over all oral
dosage form.
10. Product identification is easy and rapid requiring no
additional steps when employing an embossed and/or
monogrammed punch face.
Disadvantages of Tablet dosage form:

1. Difficult to swallow in case of children and unconscious

patients.

2. Some drugs resist compression into dense compacts, owing

to amorphous nature, low density character.

3. Drugs with poor wetting, slow dissolution properties,

optimum absorption high in GIT may be difficult to
formulate or manufacture as a tablet that will still provide
adequate or full drug bioavailability.

4. Bitter tasting drugs, drugs with an objectionable odor or

drugs that are sensitive to oxygen may require encapsulation
or coating. In such cases, capsule may offer the best and
lowest cost.
Ideal Characteristics of Tablets:

1. A tablet should have elegant product identity while free

of defects like chips, cracks, discoloration, and
contamination.

2. Should have sufficient strength to withstand mechanical

shock during its production, packaging, shipping and
dispensing.

3. Should have the chemical and physical stability to

maintain its physical attributes over time

4. The tablet must be able to release the medicinal agents in

a predictable and reproducible manner.

5. Must have a chemical stability over time so as not to

follow alteration of the medicinal agents.
Classification of Tablets
(A) Tablets ingested orally:

1. Compressed tablet, e.g. Paracetamol tablet

2. Multiple compressed tablet

3. Repeat action tablet

4. Delayed release tablet, e.g. Enteric coated Bisacodyl

tablet

5. Sugar coated tablet, e.g. Multivitamin tablet

6. Film coated tablet, e.g. Metronidazole tablet

7. Chewable tablet, e.g. Antacid tablet

(B) Tablets used in oral cavity:

1. Buccal tablet,

2. Sublingual tablet,e.g. angina pain tablet

3. Troches or lozenges

4. Dental cone

(c) Tablets administered by other route:

1. Implantation tablet

2. Vaginal tablet, e.g. Clotrimazole tablet

(D) Tablets used to prepare solution:

1. Effervescent/Dispersible tablet, e.g. Disprin tablet (Aspirin)

2. Dispensing tablet, e.g. Enzyme tablet (Digiplex)

3. Hypodermic tablet

4. Tablet triturates e.g. Enzyme tablet (Digiplex)

 TABLETS INGESTED ORALLY
1. Compressed tablet: These are uncoated tablets made by
compression of granules. These provides rapid disintegration and
drug release. e.g. Paracetamol tablet.
2. Multiple compressed tablet: These tablets are prepared to separate
physically or chemically incompatible ingredients or to produce
repeat action or prolonged action products. The ingredients of
formulation are compressed into a core tablet and the incompatible
substance with other excipients are compressed over the previously
compressed core tablet.
3. Sustained action tablet: These tablets when taken orally release
the medicament in a sufficient quantity as and when required to
maintain maximum effective concentration of drug in the blood.
4. Enteric coated tablet: These tablets are coated with the material
which does not disintegrate in stomach but passes through as it
is i.e. enteric polymer e.g.: Hydroxypropyl methyl cellulose
phthalate etc. These tablets dissolve in intestine and are site
specific.
 TABLETS INGESTED ORALLY
1. Sugar coated tablet: The compressed tablets with sugar coating
are called sugar coated tablets. It is done to mask the bitter and
unpleasant taste and odour of the medicament. It enhances the
appearance and protects the drug from atmospheric effects. e.g.
Multivitamin tablet
2. Film coated tablet: These are the compressed tablets having a
film coating of film coating polymer like hydroxy propyl cellulose,
ethyl cellulose , HPMC. It also protects the formulation from
atmospheric effects. These are tasteless, have increase in tablet
weight and have less elegance. e.g. Metronidazole tablet
3. Chewable tablet: These tablets are chewed in mouth and are
broken into small pieces. Disintegration time is reduced and
rate of absorption increases. Easily administered for infants and
elderly persons. e.g. Antacid tablet
 ORAL CAVITY TABLETS
1. Buccal Tablets: These tablets are to be placed in buccal pouch or
between the gum & lip or cheek. Tablet dissolve & disintegrated slowly &
absorb directly.
2. Sublingual Tablet: These tablets are to be placed under the longue. They
dissolve & disintegrated quickly & absorbed directly without passing into
G.I.T. Buccal and sublingual tablet should be formulated with bland
excipients, which do not stimulate salivation.
3. Lozenge tablet & troches: These tablets are designed to exert a local
effect on mouth or throat. These tablets are usually used in treatment of
sore throat or control coughing. The tablets are usually used to such drug
as anaesthetic, antiseptic and antibacterial agent, demulcent, astringent
and antitussive agent. Lozenges were earlier called pastilles.
4. Dental cones: These are relatively minor compressed tablet meant for
placing them in the empty socket after tooth extraction. Usually, these
tablets contain an antibacterial, compound which is released slowly.
Prevent the growth of bacteria. These tablets may contain an astringent
or coagulant to reduce bleeding. The base for these types is sodium
bicarbonate, sodium chloride or it may be amines acid. These cones
generally get dissolved in 20 to 40 min time.
 TABLETS ADMINISTERED BY OTHER ROUTE

1.Implantation tablet:
These tablets are placed below the skin or inserted
subcutaneously by means of a minor surgical operation and
are slowly absorbed. These must be sterile and are made by
heavy compression and fusion. e.g. Testosterone tablet.
2.Vaginal tablet:
These tablets are meant to dissolve slowly in vaginal cavity.
These are ovoid or pear shaped and are used to release
steroids, antibacterial and antiseptics etc to avoid infections.
e.g. Clotrimazole tablet.
 TABLETS USED TO PREPARE SOLUTIONS
1. Effervescent tablet:
These tablets when added in water produce effervescence. So they
dissolved rapidly in water due to the chemical reaction which takes
place between alkali bicarbonate and citric acid or tartaric acid. These
tablets are to be protected from atmospheric moisture during storage
(in well closed container). e.g. Disprin tablet (Aspirin)
2. Dispensing tablet:
These are intended to be added to a given volume of water to produce a
solution of a given concentration. The medicaments given are silver
proteinate and quaternary ammonium compounds. These are highly
toxic if taken orally and great care must be taken in packaging and
labelling. e.g. Enzyme tablet (Digiplex)
3. Hypodermic tablet:
These are compressed tablets which are composed of one or more
drugs. These tablets are dissolved in sterile water and administered
parenterally.
4. Tablet triturates:
These are small cylindrical, moulded or compressed tablets which
contains a potent medicament with a diluent. On small scale hand
operated whereas for bulk production automated machines are used.
e.g. Enzyme tablet (Digiplex)
 Compressed compression coated

Enteric coated

Bilayered Tablets
 Buccal tablets

Sublingual tablets

Lozenges
 Dental cone

D
 Vaginal tablet
Effervescent tablet

Hypodermic tablets Tablet triturate

Disintegration of tablet
Tablet Excipients
In addition to active ingredients, tablet contains a number of inert
materials known as additives or excipients. All non drug components of
a formula are termed excipients
Different excipients are:

1. Diluent

2. Binder and adhesive

3. Disintegrents

4. Lubricants and glidants

5. Colouring agents

6. Flavoring agents

7. Sweetening agents
 EXCIPIENTS IN TABLET FORMULATION
1. Diluents: The diluent is needed to increase the bulk
when quantity of medicament is very small in each
tablet. e.g. Lactose, sucrose, sodium chloride,
dextrose and starch etc.
2. Disintegrating agents: To break the tablet in smaller
particles when swallowed. These acts by three ways:
swelling, by producing effervescence and by melting at
body temperature. The disintegrating agent is divided
into two parts. One part is mixed with other excipients
before granules formation and the other is mixed with
the dry granules before compression. e.g. Potato, maize,
wheat starch etc.
3. Granulating agents: These provides moisture to convert
the fine powder into damp mass which after passing
through sieve forms granules. e.g Starch paste, acacia,
tragacanth. gelatin solution, iso propyl alcohol etc.
4. Glidants: To improve the flow properties of
granules. e.g magnesium stearate &Talc
5. Lubricants: To reduce the interparticular friction during
compression and between tablet and die wall during
ejection of tablet. e.g. Talc & magnesium stearate.
6. Binding agents: these provides strength to the granules
to keep the tablet intact and selection of which
depends on the type of tablet.e.g. gum tragacanth,
methyl cellulose etc.
7. Adsorbing agents: these are used to adsorb volatile oil,
liquid extracts and tincture etc. Prevent sticking e.g. Mg
stearate, steraric acid etc.
8. Colors, flavors and sweetening agents: All coloring
agents must be approved and certified by FDA. Two
forms of colors are used in tablet preparation – FD &C
and D & C dyes. These dyes are applied as solution in
the granulating agent or Lake form of these dyes.
 EXCIPIENTS
DILUENTS
Diluents are fillers used to increase the bulk volume of a tablet. By
combining a diluent with the active pharmaceutical ingredients, the
final product is given adequate weight and size to assist in production
and handling.
Ideal filler should fulfill a series of requirements, such as:
 Inert so as not to cause pharmacological or chemical activity of its
own
 Biocompatible with the drug substance and other excipients used in
the formulation
 Non-hygroscopic so the formulation does not absorb significant
amounts of moisture from its surroundings
 Compactable and of similar particle size to the active ingredient and
should have good dilution capacity
 Non-conducive to microbiological development
 Nontoxic, cheap, commercially available in acceptable grades, color-
compatible, have no deleterious effect on bioavailability of drugs.
 If drug product is classified as food (certain vitamin products),
excipient must be approved direct food additives
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 Lactose
• Non-reactive in anhydrous or hydrous form
• Hydrous form undergoes maillard reaction leading to browning and
discoloration of certain drugs, hence anhydrous form is preferred
• But anhydrous form picks up moisture when exposed to humidity.
• In wet granulation, hydrous lactose of two varieties are used 60-80
mesh (coarse) and 80-100 mesh (regular) grade.
• Lactose formulation show good release.
• Low cost diluent
• But may discolor in presence of amine drug bases or salts of alkaline
compounds
• Spray dried lactose
 Lactose is placed in aqueous solution, removed impurities and
spray dried
 Mixture of large alpha monohydrate crystals and spherical
aggregates of smaller crystals
 Good flowability but less compressibility
 Poor dilution potential
 Less compressibility upon initial compaction
 Problem of browning due to contamination of 5-
hydroxyfurfural which was accelerated in the presence of basic
amine drugs and catalyzedMAK95
by tartarate, citrate and acetate ions
– Fast-Flo lactose
– Spherical aggregates of microcrystals lactose monohydrate
• Held together by a higher concentration of glass
(amorphous lactose)
• Much more compressible
• Highly fluid
• Non hygroscopic
• Tablets are three to four times harder than regular spray
dried
– Tabletose: aggromerate form of lactose
• More compressible than spray dried but less
compressible than Fast Flo lactose

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 Starch
• Can be corn, wheat or potato source
• USP grade of starch has poor flow & compression characteristics
• Also has high moisture content between between 11 & 14 %.
• Specially dried starches also have standard moisture level of 2-4%
• Therefore not used in wet granulation

Starch 1500:
• Intact starch grains and ruptured starch grains that have been
partially hydrolyzed and subsequently aggromerated
• Free flowing, self lubricating, containing slightly high MC (10 %)
• Due to which does not form hard compacts
• Dilution potential is minimal, not generally used as filler-binder but
as filler disintegrant
• Retains the disintegrant properties of starch without increasing the
fluidity and compressibility of the total formulation
• Flow promoters like colloidal silicon dioxide is needed.
• Lubricants tend to dramatically soften tablets containing high
concentrations of Starch 1500MAK95
Starches
 Two hydrolyzed starches are Emdex and Celutab
which are spray crystallized
 90-92% dextrose, 3-5% maltose and the remainder
higher glucose polysaccharides
 Excellent compressibility and free flowing
 Contain 8-10% moisture and may increase hardness
after compression
 Largest particle size, therefore blending problem
may occur
Dextrose
It is also used as a tablet diluent, under the name
Cerelose, it is available as anhydrous form (when low
moisture contents are required) and a hydrate product
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Mannitol

 Exists in a number of polymorphic forms

 Not make as hard a tablet as sorbitol
 Slow solubility, non hygroscopic
 It exhibits poor flow and requires high concentrations
of lubricant
 Less sensitive to humidity
 Widely used where rapid and complete solubility is
required
 Use as a filler in chewable tablets
 Cool mouth feel but expensive

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Sorbitol
 Exists in a number of polymorphic crystalline forms
and amorphous form
 Widely used in sugar-free mints and as a vehicle in
chewable tablets
 Cool taste and good mouth feel
 Forms a hard compact
 Hygroscopic and will clump in the feed frame and
stick to the surfaces of the die table when tableted at
humidities > 50%
 Lubricant requirements increase when the MC of the
sorbitol drops below 0.5% or exceeds 2%

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Maltodextrin
Maltrin
Highly compressible
Completely soluble
Very low hygroscopic

Sucrose
• Di-Pac: cocrystallization of 97% sucrose and 3% modified
dextrin
• Small sucrose crystals glued together by dextrin
• Good flow properties and needs a glidant only when atmospheric
• moisture levels are high (>50%RH)
• Excellent color stability on aging .Concentration of moisture is
extremely critical in terms of product compressibility
• compressibility increases rapidly in a moisture range of 0.3-0.4%,
plateaus at a level of 0.4-0.5% and rises again rapidly up to 0.8%
when the product begins to cake and lose fluidity

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 • Dilution potential 20-35%
• Tablets tend to harden slightly during the first
hours after compression or when aged at high
humidities and then dried (this is typical of most
direct compression sucroses or dextroses)
Nutab:
 95.8% sucrose, 4% convert sugar (equimolecular
mixture of levulose and dextrose) and 0.1 to 0.2%
each of cornstarch and magnesium strarate
 Large particle size distribution and good fluidity
 Poor color stability

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 Cellulose
Microcrystalline cellulose (Avicel)
• The most important tablet excipient developed in modern times
• Derived from a special grade of purified alpha wood cellulose by severe
acid hydrolysis to remove the amorphous cellulose portions, yielding
particles consisting of bundles of needlelike microcrystals
• PH101 powder and PH102 are the two grades available. PH 102 is more
agglomerated, larger particle size, slightly better fluidity but not significant
decrease in compressibility
• Both grades are most compressible
• Highest dilution potential
• A strong compact is formed due to the extremely large number of clean
surfaces brought in contact during the plastic deformation and the strength
of the hydrogen bonds formed
• Extremely low coefficient of friction, no lubricant requirement
• When >20% of drugs or other excipients are added, lubrication is
necessary
• Not used as the only filler because of its cost and density
• Usually used in the conc of 10-25% as a filler-binder-disintegrant, rapid
passage of water into the compact and the instantaneous rupture of
hydrogen bonds

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 Plain MCC
– Fluidity is poor because of its relatively small particle size, small
amount of glidant are recommended in the formulations containing
high conc of MCC
– Tablets are soften on exposure to high humidities
– This softening is reversible when tablets are removed from the humid
environment
– >80% MCC may slow the dissolution rates of AI having low water
solubility
– Small particles get physically trapped between the deformed MCC
particles, which delays wetting and dissolution
– This phenomenon can be overcome by adding portions of water soluble
excipient
Inorganic calcium salts
• Dicalcium phosphate (Emcompress or DiTab)
– Free flowing aggregates of small microcrystals that shatter upon compaction
– Inexpensive and possesses a high degree of physical and chemical stability
– Non hygroscopic at a RH of up to 80%
– Good fluidity,Slightly alkaline with a pH of 7.0 to 7.3
– Precludes its use with AI that are sensitive to even minimal amounts of
alkalinity
• Tricalcium phosphate (TriTab) is less compressible and less soluble, higher ratio
of calcium ions MAK95
 Binders and Adhesives
1. Used in tablet formulations to make powders more
compressible and to produce tablets that are more resistant
to breakage during handling.
2. In some instances the binding agent imparts viscosity to the
granulating solution so that transfer of fluid becomes
difficult.
3. This problem can be overcome by adding some or all binding
agents in the dry powder prior to granulation.
4. For granulation, solutions of adhesive materials like acacia,
gelatin, liquid glucose, sucrose syrup, starch paste etc. are
employed to appropriate extents
5. Solutions of methyl cellulose, CMC and mucilage of
naturally occurring gums and colloidal clays are used in
most recent times.

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 Binders and Adhesives
1. For water sensitive drugs, solutions of PVP, EC, HPMC etc,
in alcohol or other organic solvents are used.
2. A 10% dispersion of partially hydrolyzed starch is
commonly applied in industry as it is a good adhesive, has
less retardant effect on disintegration and dissolution in
comparison to other additives.
3. The heating and cooling of the starch paste can be controlled
at precise rate which enables to control degree of hydrolysis
of starch causing less batch to batch variation.
4. Some substances possess adhesiveness of their own and
hence can be just granulated with ethyl alcohol as binder.
5. Binding agents such as MCC, amylose, colloidal clays, finely
powdered acacia are used in dry granulation to afford
adhesion in slugging operations.

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 Disintegrant
• Disintegrants, an important excipient of the tablet
formulation, are always added to tablet to induce
breakup or disintegration of tablet when it comes in
contact with gastro intestinal 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.
• Disintegrants may function by drawing water into the
tablet, swelling and causing the tablet to burst apart.
• This is very critical for drug bioavailability.
• Starch USP and various starch derivatives are used as
disintegrants in the conc range of 5-20% of tablet weight.
• Modified starches like Primogel and Explotab, which are
low substituted carboxylmethyl starches are used in lower
conc. (1-8% with 4% as optimum).
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 •Pregelatinized starch (5 % conc.)
Sodium carboxy methylcellulose (NaCMC) 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 (Ac-di-Sol) 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
List ofwater.
disintegrants
DISINTEGRANTS CONCENTRATION IN SPECIAL COMMENTS
GRANULES(%)
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
Explotab® 2-8 Sodium starch glycolate,
superdisintegrant.
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AC-Di-Sol® 1-3 Direct compression
 Lubricants, Antiadherents & Glidants
In tablet manufacturing one faces the problem of flow of
granules from the hopper into the die cavity, sticking of
material to the punches and die walls and release free
movement of the compressed tablets from the die cavity.
To overcome these difficulties
1. Lubricants are the substance which prevent adhesion of the
tablet material to the surface of the dies and punches, reduce
interparticle friction, facilitate an easy ejection of tablets from
the die cavity and improves rate of flow of tablet granulation.
Commonly used lubricants are talc, magnesium stearate,
calcium stearate, stearic acid, hydrogenated vegetable oil
and PEG. The method of adding lubricant is an important
factor for satisfactory results. The quantity of lubricant
significantly varies from 0.1 to 5%.
2. .
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 Lubricants, Antiadherents & Glidants
1. A glidant is a substance that improves the flow characteristics
of a powder mixture. These materials are always added in the
dry state just prior to compression. The most commonly used
glidants are colloidal silicon dioxide (Cabosil®, Cabot®)
and asbestos free talc. They are used in concentration less
than 1%. Talc is also used and may serve the dual purpose of
lubricant/glidant.
2. 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.
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Lubricants Conc Comments
Stearates(Magnesium Stearate, List
0.25 -1 ofReduce
LAG’s tablet strength; prolong disintegration;
Calcium Stearate, Sodium stearate) widely used.

Talc 1 -2 Insoluble but not hydrophobic; moderately

effective.
Glycerylbehapate(Compritol888) 1-5 Both lubricant and binder;

Antiadherants Range Comments

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

Glidants Range

Colloidal silica i.e. syloid, pyrogenic silica 0.25%

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Hydrated sodium silioaluminate 0.75%
 Colors, flavours and sweeteners
Colors
1. Disguising off-colored drugs
2. Product identification
3. Elegant look

• Natural vegetable colors – limited availability & unstable

• FD&C and D&C approved dyes are used.
• Either added in dry granulation mix or in vehicle used for wet
granulation.
• Wet granulation gives better uniformity of color, but migration
of the dye to the top of granules along with solvent during
drying should be watched .
• Lake dyes( dyes absorbed on alumina or aluminium
hydroxide) are used in dry granulation.
• Dyes tend to fade on standing and exposure to light leads to
mottling.
• Eg. FD&C approved lakes and dyes – lake sunset yellow,
brilliant blue, ferric oxide.
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 Flavors
 Flavours are usually limited to chewable tablets or other tablets
intended to dissolve in the mouth.
 In general flavours that are water soluble have been found little
acceptance in manufacturing of tablets because of there poor
stability.
 Flavouring agents do not affect any physical characteristics of
the tablet granulation.
 Flavours can be incorporated by spraying them on to the
granules in the form of solutions in some volatile organic
solvent.
 Also can be incorporated with lubricants
 Proportion limited to 0.5 %
 Excess quantity will interfere with free flow of granules
 e.g. Raspberry, Pineapple, Peppermint, Blackcurrant, Orange,
Mango, Strawbery

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 Sweeteners

Use is primarily limited to chewable tablets

Mannitol – 72% as sweet as sucrose
Earlier saccharin was the only artificial sweetener used.
Its is 500 times sweeter than sucrose but has a bitter
aftertaste and also carcinogenic properties
Aspartame is the new sweetener- disadvantage is its
instability in the presence of moisture.

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 Tableting methods
• Dry methods
– Direct compression (Dry blending)
– Compression granulation (dry)
• Wet methods
– Wet granulation

DRY WET
DRY BLENDING GRANULATION GRANULATION

WEIGHING
WEIGHING WEIGHING
SIZING
SIZING SIZING
GRANULATION
BLENDING BLENDING
DRYING
LUBRICATION COMPACTION
BLENDING
COMPRESSION MILLING
LUBRICATION
COATING LUBRICATION
COMPRESSION
COMPRESSION
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 Rationale for granulating powders
1. To prevent segregation of the constituents of the
powder blend.
2. To improve flowability of the powder mixture.
3. To improve the compaction characteristics of the
powder mixture due to better distribution of the
binder within the granules.
4. To improve homogeneity and thus ensure content
uniformity of powder blend.
Wet Granulation

1. The most popular method employed for the production of

compressed tablets (over 70% of formulation in tablet

manufacture is wet granulation).

2. This due to the greater probability that the granulation will

meet all the physical requirements for the compression of

good tablets.

3. Its chief disadvantages are the number of separate steps

involved, as well as the time and labor necessary to carry out

the procedure, especially on a large scale.

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Weighing and mixing:
1. The active ingredient, diluent and disintegrants are mixed or
blended well.
2. The powder blend may be sifted through a screen to remove or
break up lumps, this screening affords additional mixing.
3. The screen selected always should not affect the potency of the
ingredients through interaction. For example, the stability of
ascorbic acid is affected deleteriously by even small amounts of
copper, thus care must be taken to avoid contact with copper or
copper-containing alloys

49
Granulation: The wet granulate is prepared by adding the binder
solution to facilitate adhesion of the powder particles forming a damp
mass resembling dough.
1. Solutions of the binding agent are added to the mixed powders with
stirring.
2. The powder mass is wetted with the binding solution until the damp
mass has the consistency of a dough.
3. If the granulation is over wetted, the granules will be hard, requiring
considerable pressure to form the tablets, and the resultant tablets
may have a mottled appearance.
4. If the powder mixture is not wetted sufficiently, the resulting granules
will be too soft and friable, breaking down during lubrication and
causing difficulty during compression.
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Screening:

1. The wet screening of the damp mass into pellets or

granules is done by pressing through a screen or
granulating sieve (6-8 mesh), by hand or with special
equipment that prepare the granules by extrusion
through perforations in the apparatus.
Drying:
1. Tray drying was the most widely used method of drying tablet
granulations in the past, Notable among the newer methods
being introduced are the fluid-bed dryers.
2. In fluidization, the material is suspended and agitated in a warm
air stream while the granulation is maintained in motion.
3. Comparing the fluidized bed dryer and a tray dryer indicated that
the former was 15 times faster than the conventional method of
tray drying.
4. In addition to the decreased drying time, the fluidization method
have advantages such as better control of drying temperatures,
decreased handling costs and the opportunity to blend lubricants
and other materials into the dry granulation directly in the
fluidized bed.

52
5. In drying, it is desirable to maintain a residual amount of moisture in

the granulation. This is necessary to maintain the various granulation

ingredients such as gums in a hydrated state. Also, the residual moisture

contributes to the reduction of the static electric charges on the

particles.

6. In the selection of any drying process, an effort is made to obtain a

uniform moisture content. In addition to the importance of moisture

content of the granulation in its handling during the manufacturing

steps, the stability of the products containing moisture-sensitive active

ingredients may be related to the moisture content of the products.53

7. Previously it was indicated that water-soluble colorants can
migrate toward the surface of the granulation during the drying
process, resulting in mottled tablets after compression.
8. This is also true for water-soluble drug substances, resulting in
tablets unsatisfactory as to content uniformity.
9. Migration can be reduced by drying the granulation slowly at
low temperatures or using a granulation in which the major
diluent is present as granules of large particle size. The presence
of microcrystalline cellulose in wet granulations also reduces
migration tendencies.

54
• Dry screening: After the granules are dried, they are passed
through a screen of smaller size than the one used for the wet
mass to select granules of uniform size to allow even fill in the
die cavity. It usually is screened through 60- or 100-mesh to
eliminate small lumps as well as to increase the covering power
of the lubricant.
• The presence of some fines is necessary for the proper filling of
the die cavity.
• Lubrication : A dry lubricant, antiadherent and glidant is
added to the granules either by dusting over the spread-out
granules or by blending with the granules. Dry binder, colorant
or disintegrant may be also added in this step.
• Compression or Tableting: Last step in which the tablet
material is fed into the die cavity and then compressed.

55
• Advantages:
1. ¨ Reduced segregation of formulation components
during storage and/or processing
2. ¨ Useful technique for the manufacture of tablets containing
low and or high concentrations of therapeutic agent
3. ¨ Employs conventional excipients and therefore is not
dependent on the inclusion of special grades of
excipients
• Disadvantages:
1. Often several processing steps are required
2. Solvents are required in the process: this leads to a number of
concerns:
a. Drug degradation may occur in the presence of the solvent.
b. The drug may be soluble in the granulation fluid.
c. Heat is required to remove the solvent.
 Wet Granulation Equipments
Traditionally, dry mixing prior to granulation in wet
granulation process has been carried out using
I) Shear granulator
 Sigma blade mixer,
 Heavy-duty planetary mixer.

Sigma blade mixer Planetary mixer

MAK95
High shear mixture has been widely used in
Pharmaceutical industries for blending and
granulation.
• Wet agglomeration in a high-shear mixer
involves typically 3 phases:
• Dry Powder mixing ( 2-5 mins)
• Liquid binder addition (1-2 mins)
• Wet massing
• Advantages:
• Highly cohesive material can be granulated.
• Disadvantages:
• Mechanical degradation.
II. High Speed mixers/Granulators
Littleford Lodige mixers
Plow-shaped Chopper blades
mixing tool

MAK95
 Littleford Lodige mixers

• Consists of a horizontal cylindrical shell

equipped with a series of plow-shaped mixing
tools
• One or more high-speed blending chopper
assemblies mounted at the rear of the mixer.
• For the addition of liquid, an injection tube
terminating in one or more spray nozzles is
provided.
• Complete mixing occurs in 30-60 sec.
 Diosna mixer/Granulator

• Uniform distribution of all formulation ingredients.

• Short mixing and granulation time.
• Useful working capacity of upto 80% to 40% of
bowl volume.
• Uniform granules by gentle processing.
• Wide range of applications.
• Easy scale up & Scale down between machine sizes.
• Bowl shape design to have no dead spaces.
 Diosna
mixer/granulator
Chopper blades Mixer blades

MAK95
Gral mixers/granulator
1. In Gral mixer, mixing bowl may
be loaded at floor level and
then raised with a cover
providing tight seal.
2. Provide sufficient space for the
loading and unloading of the
container.
3. Major adv is the main mixing
blade is not a part of the bowl
thus making cleanup easier.
4. Fluid may be injected into the
mixer bowl.
5. Time control can be possible in
the equipment.
Gral mixers/granulator Chopper blade

Three-bladed
mixing shaft
Fluidized Bed Granulator
 Fluidized Bed Granulator
• The powder particles are fluidized in a stream of
air.
• Granulation fluid is pumped from a reservoir
and sprayed from a nozzle on to the bed of
powders.
• Heated and filtered air is blown through the bed
of unmixed powders to fluidize the particles and
mix the powders.
• The fluid causes the primary powder particles to
adhere when the droplets and powders collide.
 Fluidized Bed Granulator
• Sufficient liquid is sprayed to produce granules of the
required size, at which point the spray is turned off
but the fluidizing air continued.
• The wet granules are then dried in the heated
fluidizing air stream.
• Advantages
• It reduces product loss.
• It improves worker safety.
• Disadvantages
• time consuming.
• Difficulty of assuring reproducibility
The entire process of granulation to be completed in single
equipment fluid bed granulator. It performs the following steps;
- Blending (drug + excipients e.g. filler & disintegrant)
-Granulation (fluidized bed powder mix is sprayed by binder
solution).
- Drying to the desired moisture content.

Binder solution spray Fluid-bed granulator

Granulation
of the powder

Warm air flow

MAK95
• DRY GRANULATION
1. This method is referred to as dry granulation, pre
compression or double-compression. It eliminates
a number of steps but still includes weighing,
mixing, slugging, dry screening, lubrication and
compression
2. By the dry granulation method, the powder
mixture is compacted in large pieces and
subsequently broken down or sized into granules.
3. For this method, either the active ingredient or
the diluent must have cohesive properties
4. Dry granulation is especially applicable to
materials that cannot be prepared by wet
granulation because they degrade in moisture
or the elevated temperatures required for drying
the granules.
 Advantages
1. These methods are not generally associated with
alterations in drug morphology during
processing.
2. No heat or solvents are required.
3. If the drug dose is too high for DC
4. Drug is sensitive to heat, moisture or both
e.g (aspirin & multi vitamin)
5. Dry powder blend that cannot be directly
compressed because of poor flow or compression
properties.
 Disadvantages
1. Specialist equipment is required for
granulation by roller compaction.
2. Segregation of components may occur mixing.
3. There may be issues regarding powder flow.
4. The final tablets produced by dry granulation
tend to be softer than those produced by wet
granulation
5. Slugging and roller compaction lead to the
generation of considerable dust.
SLUGGING
1. After weighing and mixing the ingredients, the
powder mixture is slugged, or compressed, into
large flat tablets or pellets about 1 inch in
diameter.
2. The slugs are broken up by hand or by a mill
and passed through a screen of desired mesh
for sizing.
3. Lubricant is added in the usual manner, and
tablets are prepared by compression.
4. Aspirin, which is hydrolyzed on exposure to
moisture, may be prepared into tablets after
slugging.
SLUGGING

1. It involves the compaction of tablet formulation by

means of tablet press followed by milling and
screening, prior to final compression of tablets.
2. Blend is forced into dies of large capacity tablet
press and compacted using flat faced punches.
These compacted masses are called slugs and
process is called slugging.
3. Slugs are then milled or screened to produce good
free flowing granules for compression. The process
of Slugging, Screening and Milling can be repeated
till desired characteristics of flow are obtained.
MAK95
 SLUGGING
1. This is done on a tablet press designed for slugging,
which operates at pressures of about 15 tons,
compared with a normal tablet press, which operates
at pressure of 4 tons or less.
2. Slugs range in diameter from 1 inch, for the more
easily slugged material, to ¾ inch in diameter for
materials that are more difficult to compress and
require more pressure per unit area to yield
satisfactory compacts.
3. If an excessive amount of fine powder is generated
during the milling operation the material must be
screened & fines recycled through the slugging
operation.
4. The repeat process of compaction pressure causes
strengthening of the bonds that holds the tablet
together.
MAK95
 Dry compaction/Roller compaction
1. On a large scale compression granulation can also be
performed on a roller compactor.
2. Granulation by dry compaction can also be achieved
by passing powders between two rollers that compact
the material at pressure of up to 10 tons per linear
inch.
3. Materials of very low density require roller
compaction to achieve a bulk density sufficient to
allow encapsulation or compression.
4. One of the best examples of this process is the
densification of aluminum hydroxide.
5. Roller compactor is capable of producing as much as
500 kg/hr of compacted ribbon like materials which
can be then screened and milled in to granules for
compression.

MAK95
1. Roller compaction basically
consists of three steps, i.e.,
powder feeding, pre-densification
and ribbon formation.
2. During the feeding step, the
powder material is fed into two
counter-rotating rolls by either
gravity or force-feed screws.
3. Once the powder material is
drawn into the nip angle area, it
rubs against the roll surface and
undergoes the pre-densification
process.
4. As the material enters the roll
gap, particles are deformed or
fragmented to form ribbons under
hydraulic pressure.
5. The ribbons are then sized
through screens to produce
granules to be compressed into
MAK95tablets or filled into capsules.
 Limitations of dry granulation
1- Dry granulation often
produces a higher
Powder to be percentage of fines or non
compacted
compacted products,
Compacts
which could compromise
the quality or create yield
problems for the tablet.
Size reduction of
compacts into 2- It requires drugs or
granules
excipients with cohesive
properties.
Roller compactor
"Chilsonator"

MAK95
Chilsonator
Direct Compression

1. Direct compression consists of compressing tablets

directly from powdered material without modifying
the physical nature of the material itself.
2. Reserved for a small group of crystalline chemicals
having all the physical characteristics required for the
formation of a good tablet. This group includes
chemicals such as potassium salts (chlorate, chloride,
bromide, iodide, nitrate, permanganate), ammonium
chloride.

84
1. For tablets in which the drug itself constitutes a major
portion of the total tablet weight, it is necessary that
the drug possess those physical characteristics required
for the formulation to be compressed directly.
2. Direct compression for tablets containing 25% or less of
drug substances frequently can be used by formulating
with a suitable diluent which acts as a carrier or vehicle
for the drug.

85
• These properties are imparted to them by a
preprocessing step such as, spray drying, or
crystallization.

• These vehicles include processed forms of most of the

common diluents including dicalcium phosphate
dihydrate, tricalcium phosphate, calcium sulfate,
anhydrous lactose, spray-dried lactose, pregelatinized
starch, compressible sugar, mannitol and microcrystalline
cellulose.

86
• These commercially available direct- compression vehicles may

contain small quantities of other ingredients (e.g, starch) as

processing aids .e.g. Dicalcium phosphate dihydrate (Di-Tab,)

• The chemical is odorless, tasteless and non- hygroscopic. Since

it has no inherent lubricating or disintegrating properties, other

additives must be present to prepare a satisfactory

formulation.

87
• Compressible sugar consists mainly of sucrose that is

processed to have properties suitable for direct compression.

It also may contain small quantities of dextrin, starch or

invert sugar. It is a white crystalline powder with a sweet

taste and complete water solubility. It requires the

incorporation of a suitable lubricant at normal levels for

lubricity. The sugar is used widely for chewable vitamin

tablets because of its natural sweetness.

88
• One commercial source is Di-Pac (Amstar) prepared by the

cocrystallization of 97% sucrose and 3% dextrins.

• Some forms of lactose meet the requirements for a direct-

compression vehicle. Hydrous lactose does not flow and its use

is limited to tablet formulations prepared by the wet

granulation method, Both anhydrous lactose and spray dried

lactose have good flowability and compressibility and can be

used in direct compression provided a suitable disintegrant and

lubricant are present.

89
 Microcrystalline cellulose (Avicel, FMC).
1. This non fibrous form of cellulose is obtained by spray-
drying washed, acid-treated cellulose and is available in
several grades which range in average particle size from 20 to
100 um. It is water insoluble but the material has the ability
to draw fluid into a tablet by capillary action;

2. It swells on contact and thus acts as a disintegrating agent.

The material flows well and has a degree of self-lubricating
qualities, thus requiring a lower level of lubricant as
compared to other excipients.

90
 Direct compression

 Tablets are compressed directly from powder blends

of the active ingredient and suitable excipients
 No pretreatment of the powder blends by wet or dry
granulation procedures is necessary
 Additives:
 Diluents
 Disintegrating agents
 Organoleptic additives
 Glidants, anti-adhesives,lubricants

MAK95
Powders intended for compression into tablets must possess two
essential properties
Powder fluidity or flowability
• The material can be transported through the hopper into the
die
• To produce tablets of a consistent weight
• Powder flow can be improved mechanically by the use of
vibrators, incorporate the glidant
Powder compressibility
• The property of forming a stable, intact compact mass when
pressure is applied is called powder compressibility
Easily mixed with other particles
Homogenous colouring etc
Friction and adhesion properties
MAK95
Step I. Weighing – Active ingredient & excipients
Step II. Sizing – excipients and API passed through different
mesh sizes - For eg. 40#, 60#, 80#, 100#, 200# & 250#
Step III. Blending – Powders to be used for encapsulation or
to be granulated or directly compressed must be well blended
to ensure good drug distribution.
 Inadequate blending at this stage could result in discrete
portion of the batch being either high or low in potency.
 Steps should also be taken to ensure that all the ingredients
are free of lumps and agglomerates.
 For these reasons, screening and/or milling of the ingredients
usually makes the process more reliable and reproducible.
Step IV. Lubrication – addition of lubricants, glidants or anti
adherents
Step V. Compression
Step VI. Coating
MAK95
Things to consider at blending stage
 Homogeneity
 Risk of over mixing
 Can lead to demixing
 Influence by properties of the particles
 High shear rates
• Effects the particle size in weak powders
• Scaling up
• Not always linear

MAK95
Problems related to elimination of granulation process
in Direct Compression
1. The variables faced in the processing of the
granules can lead to significant tableting problems.
2. 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.
3. 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.
4. Drying can lead to unblending as soluble API
migrates to the surface of the drying granules.
 Advantages of direct compression:
Industry view point:
I. Commercial availability of the directly compressible excipients
possessing both good compressibility and good flowability. For
example, Spray dried lactose, Anhydrous lactose, Starch-1500,
microcrystalline cellulose, Sorbitol
II. Major advances in tablet compression machinery:
i) Improved positive die feeding,
ii) Precompression of powder blend.
Economy: Fewer manufacturing steps and pieces of equipment,
reduce labor costs, Less process validation, Lower 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. MAK95
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.

MAK95
 Disadvantages of direct compression:
1. Differences in particle size and bulk density between drug
and diluent may lead to stratification with in the granulation
leading to poor drug content uniformity in the tablets
2. Large dose of drug may present problems if the drug is not
easily compressible.
3. Problems in the uniform distribution of low dose drugs.
4. Diluent may interact with the drug. E.g. amine compound and
spray dried lactose which can be seen by a yellow
discoloration
5. Direct compression process may lead to static charge buildup
during routine screening and mixing which may prevent
uniform distribution of drug.

MAK95
 Equipments used for Mixing, blending and lubrication

 High share mixers

 Tumbling mixers
 Y-cone
 Rotating cube
 Double cone
 Fluidized bed
 Agitator mixers
 Ribbon blender

MAK95
Equipments used in sieving

MAK95
 Tablet Compression
Tableting Compression Machine
Tablets are made by compressing a
formulation containing a drug or drugs with
excipients on stamping machine called
presses. Tablet presses are designed with
following basic components:
3 important steps for tablet compression
1. Filling
2. Compression
3. Ejection
Single punch machine
• The compression is applied by the
upper punch
• Stamping press
 Common stages occurring during compression

 Stage 1: Top punch is withdrawn from the die by the

upper cam. Bottom punch is low in the die so powder
falls in through the hole and fills the die
 Stage 2: Bottom punch moves up to adjust the powder
weight-it raises and expels some powder
 Stage 3: Top punch is driven into the die by upper cam.
Bottom punch is raised by lower cam. Both punch heads
pass between heavy rollers to compress the powder
 Stage 4: Top punch is withdraw by the upper cam.
Lower punch is pushed up and expels the tablet. Tablet is
removed from the die surface by surface plate
 Stage 5: Return to stage 1
 Tablet compression machines
1. Hopper for holding and feeding granulation
to be compressed
2. Dies that define the size and shape of the
tablet
3. Punches for compressing the granulation
within the dies
4. Cam tracks for guiding the movement of the
punches
5. Feeder, a feeding mechanisms for moving
granulation from the hopper into the dies
Single Punch
Machine (Tablets)

Upper and
Lower Collar

Collar locker
 Multi-station rotary press
• The head of the tablet machine that holds the
upper punches, dies and lower punches in
place rotates
• As the head rotates, the punches are guided
up and down by fixed cam tracks, which
control the sequence of filling, compression
and ejection.
• The portions of the head that hold the upper
and lower punches are called the upper and
lower turrets.
• The portion holding the dies is called the die
table
• Granules from hopper empty in the feed
frame (A) containing several interconnected
compartments.
• These compartments spread the granulation
over a wide area to provide time for the dies
(B) to fill
• The pull down cam (C) guides the lower
punches to the bottom, allowing the dies to
overfill
• The punches then pass over a weight-control
cam (E), which reduces the fill in the dies to
the desired amount
• A swipe off blade (D) at the end of the feed
frame removes the excess granulation and
directs it around the turret and back into the
front of the feed frame
• The lower punches travel over the lower
compression roll (F) while simultaneously the
upper punches ride beneath the upper
compression roll (G).
• The upper punches enter a fixed distance into
the dies, while the lower punches are raised
to squeeze and compact the granulation
within the dies
• After the moment of compression, the upper
punches are withdrawn as they follow the
upper punch raising cam (H)
• The lower punches ride up the cam (I) which
brings the tablets flush with or slightly above
the surface of the dies.
• The tablets strike a sweep off blade affixed to
the front of the feed frame (A) and slide down
a chute into a receptacle
• At the same time, the lower punches re-enter
the pull down cam (C) and the cycle is
repeated
feed frame (A) , dies (B), pull down cam (C) , weight-control cam (E),
swipe off blade (D) , lower compression roll (F), upper compression roll
(G), upper punch raising cam (H), cam (I)
• Although tablet compressing machinery has
undergone numerous mechanical
modifications over the years, the compaction
of materials between a pair of moving
punches within a stationary die has remained
unchanged
• The principle modification from earlier
equipment has been an increase in production
rate which is regulated by
– Number of tooling sets
– Number of compression stations
– Rotational speed of the press
• Special adaptations of tablet machines allow
for the compression of layered tablets and
coated tablets
• A device that chills the compression
components to allow for the compression of
low-melting point substances such as waxes
i.e. suppositories
• Although tablet compressing machinery has undergone
numerous mechanical modifications over the years, the
compaction of materials between a pair of moving punches
within a stationary die has remained unchanged
• The principle modification from earlier equipment has been an
increase in production rate which is regulated by
– Number of tooling sets
– Number of compression stations
– Rotational speed of the press
• Special adaptations of tablet machines allow for the compression
of layered tablets and coated tablets
• A device that chills the compression components to allow for the
compression of low-melting point substances such as waxes i.e.
suppositories
MAK95
Rotary Tablet Press
HIGH SPEED ROTARY
DOUBLE ROTARY MACHINE
MACHINE

MAK95
SINGLE ROTARY MACHINE

MAK95
 Physics of compression
1. A tablet is formed by reducing tile volume of a set of
autonomous particles until they are consolidated into
a solid body
2. Tablet consolidation occurs when the punches and die
go between two compression rollers
3. The complete tablet manufacturing cycle occurs in
four steps:
(I) the die is filled,
(ii ) the fill weight is adjusted,
(iii) the tablet is compacted. and
(iv) the tablet ejected from the die .

4. From a material point of view, a compaction process is

normally described by a series of sequential phases
MAK95
MAK95
1. Initially as the volume is reduced. the
particles rearrange into a closer packing
structure.
2. At a certain point, the packing
characteristics of the particles and inter
particulate friction between particles will
prevent any further particle rearrangement.
3. At this point the further reduction in
compact volume results in the elastic,
viscoelastic and plastic deformation of the
particles.
4. Elastic deformation is reversible, whereas
the plastic deformation is irreversible.
MAK95
 • In addition, particle
fragmentation
or breakage results in smaller
particles, which further decreases
in compact volume.
• As the volume is further reduced,
the smaller particles formed by
fragmentation can undergo
deformation.
• As a consequence of these
processes, particle surfaces are
brought into close proximity to
each other which can lead to the
formation of inter particulate
bonds.
• These bonds may later break,
which facilitates further
compression. MAK95
 To summarize, the following processes are involved in
the compaction of a powder:
1. Particle rearrangement
2. Elastic, viscoelastic and plastic deformation of particles
3. Fragmentation of particles
4. Formation of interparticulate bonds
During tablet formation the following types of bond
mechanisms are hypothesized to occur:
1. Mechanical interlocking (between irregularly shaped
particles)
2. Inter particulate attraction force s (e.g., intermolecular
forces, such as Van der Waal forces, electrostatic forces
and hydrogen bonding)
MAK95
3. Solid bridges (due to melting)
• In tableting, compact formation occurs due to inter
particulate attraction that arises from intermolecular
bonding forces that act over very short period
• As the powder bed is consolidated and the particles
start to deform around each other this leads to a
mechanical interlocking of the particles and this also
increases the number of contact points between the
particles.
• The dominant interaction force between solid
surfaces is the Van der Waals force of attraction and
hydrogen bonding may occur intra and
intermolecularly.

MAK95
• In addition, the applied load gets transmitted from
particle to particle
through contact points, the pressure at these points
can be very high.
• This may cause heating with a possibility of localized
melting, especially of low-melting point solids.
• Upon unloading, the reduction of local stress at the
point of contact could lead to reso1idification,
forming a solid bridge between the particles.
• Hence solid bridges that contribute to the overall
compact strength can be defined as areas of real
contact, i.e., contact at an atomic level between
adjacent surfaces in the compact.