Course Name: Pharmaceutics-II

Course Code: Pharm-3101

Topic: Tablets
Instructor: Dr Mohammad Didare Alam
Muhsin
PhD (QUT Australia), BPharm (Hons), MPharm (JU)

Professor
Department of Pharmacy, JU
Email: muhsin_ju@yahoo.com
Contact: +8801866 489 828
Outline
• Tablets – Definition, Properties, Advantages &
Disadvantages
• Tablet Formulation/Tablet Ingredients
• Different types of tablet: brief introduction,
merits/demerits, uses
• Tablet compression: Tablet machine components,
stages of tablet compression, physics of tablet
making (compaction, compression and
consolidation), Different methods of tablet
compression (direct compression, dry granulation
and wet granulation)
• Flow Characteristics of Granules: importance of
flowability, Factors affecting granule/powder flow,
bulk density —definition and estimation,
assessment of flowability
• Processing problems of tablet making
• Evaluation of tablets
 Tablets – Definition, Advantages &
Disadvantages
Definition:
• Tablets may be defined as solid dosage forms
containing drug substances with/without
excipients prepared by compression or molding.
• Tablets are mostly intended for oral
administration.
Advantages:
1. Are in unit dosage form and offer greatest dose
precision and least content variation (among all
oral dosage forms).
2. Lowest cost (of all oral forms)
3. Lightest and most compact (of all oral forms).
4. Easiest and cheapest (of all oral forms) to pack,
ship and dispense (among all oral forms).
5. Easiest to swallow with least tendency for hang-
up.
6. Can be designed in some special release forms
Continued…

7. Allows for simple and economic mass production

with robust, consistent quality and elegant
outlook.
8. Best combination of physical, chemical and
microbiological stability of all oral forms.
9. Allows for masking offending taste or odour by
coating.
10.Allows for simplest and cheapest way of putting
identification marking by using an embossed or
monogrammed punch (without any additional
steps) .
Assignments:
• “One of the major advantages of tablets over
capsules is that tablet is an essentially tamper-
proof dosage form” – Explain.
• “A major disadvantage of capsules over tablets is
their higher cost” – Explain.
 Continued…

Disadvantages:
1. Some drugs resist compression into dense
compacts due to their amorphous nature or
flocculent, low-density character.
2. Not suitable for drugs with poor solubility, poor
absorption properties or instability in GI tract.
3. Drugs with offending taste/odour or sensitive to
oxygen/moisture may require
encapsulation/coating before/after compression.
In such cases, capsules may offer the best and
lowest cost approach.
4. Some drugs irritate or may otherwise harm GI
mucosa.
5. May be difficult to swallow for children or elderly
patients.
Assignment: Give general advantages and
Disadvantages of (a) Solid dosage forms (b)
oral dosage forms.
 Tablet Ingredients
Tablet formulation = Drug(s) (active ingredient(s)) + Excipients
(Additives)
Various Excipients Used in Tablet formulation:
• Diluents/Fillers/Bulking agents
• Binders and Adhesives
• Disintegrants
• Lubricants, Antiahherents and Glidants
• Colouring, Flavouring and Sweetening agents
Diluents
• Diluents are used to make up the required bulk of the tablet when the
drug dosage itself is not adequate to produce this bulk.
• Secondary reasons: to impart other properties such as improved
cohesion, direct compression or improved flow.
Ideal characteristics of a diluent:
i) Be inert and biocompatible.
ii) Cheap and available.
iii) Be non-hygroscopic.
iv) Should not affect the bioavailability of the drug.
v) Be stable alone and in combination with drugs.
vi) Be free from unacceptable microbiologic load.
vii) Have an acceptable taste.
viii) Be colour compatible.
ix) Not contraindicated by themselves (eg, sucrose) or because of a
component (eg, Na) in any segment of population.
x) Be acceptable to regulatory bodies.
Some commonly used diluents: ???
 Continued…
Binders & Adhesives:
• These materials are added to drug-filler mixture either dry or in
solution form (solution binder) to promote adhesion of particles in
order (a) to form granules during wet granulation or (b) to form
cohesive compacts for directly compressed tablets.
• Binders ensure required mechanical strength of granules and final
tablets.
• They are added to the formulation at a relatively low concentration
(typically 2-10% by weight).
• Solution binders are generally considered the most effective and is
the most common way of incorporating a binder into granules.
Some commonly used binders: ???

Disintegrants:
• These agents are added to most tablet formulations to facilitate
breaking or disintegration of the tablet in contact with water in the
GIT.
• Disintegrants may be added prior to or after the granulation
process.
• Disintegrants may function by drawing water into the tablet,
swelling and causing the tablet to burst apart.
• Disintegration of the tablet may be critical to the subsequent
dissolution of the drug and in turn attainment of satisfactory drug
 Continued…

Fig.: Drug release process from a tablet by disintegration and

dissolution
Ref: Aulton
 Continued…
Lubricants, Glidants and Antiadherents:
• These 3 classes of materials are typiclly described together because
they have overlapping functions.
• Lubricants are intended to reduce the friction between the walls of the
tablet and the walls of the die cavity during tablet ejection .
• Antiadherents are intended to reduce adhesion/sticking of tablet
granulation or powder to punch faces or to the die wall.
• Glidants (flow promoters) are intended to promote the flow of the tablet
granulation or powder materials by reducing the friction between
particles.
Some Commonly Used Lubricants, Glidants and
Antiadherents: ???
Colouring Agents:
• Colours and dyes are intended for one or a combination of following
purposes:
 Disguising of off-colour drugs
 Product identification &
 Production of a more elegant product.
• They are added to tablet formulations in either of two forms:
 As a solution in the granulating agents
 As a colour lake blended with other dry ingredients
(Lake is an insoluble form of dye produced by adsorbing a water soluble
dye to a hydrous oxide of a heavy metal).
Some Commonly Used Colouring Agents: ???
 Continued…
Flavouring Agents:
• Flavouring agents are incorporated into a tablet formulation to give the
tablet a more pleasant flavour or to mask an unpleasant one.
• Their use is usually limited to chewable tablets or other tablets
intended to dissolve in the mouth.
• Flavouring agents used in tablets are mostly flavour oils. Some dry
flavours are also available.
• Flavour oils can be (a) mixed with tablet granulations as an alcoholic
solution, (b) dispersed on clays or other absorbents, or (c) emulsified in
aqueous granulating agents.
• The maximum amount of flavour oil that can be added to tablets is 0.5
to 0.75%.
Commonly used flavouring agents: ???
Sweetening Agents:
• The use of sweeteners is primarily limited to chewable tablets and are
intended to exclude or limit sugar (eg, mannitol) in the tablet.
Commonly used sweetening agents: ???
Miscellaneous additives:
• Matrix former
• Dissolution enhancer
• Absorption enhancer
• Sorbent
 Types of Tablet
A) Oral Tablets for Ingestion
• Compressed tablets (CT)
• Multiple compressed tablets (MCT)
 Layered tablets
 Compression-coated tablets
• Repeat-action tablets
• Delayed action and enteric-coated tablets
• Film-coated tablets
• Chewable tablets
B) Tablets Used in the Oral Cavity
• Buccal tablets
• Sublingual tablets
• Troches and lozenges
• Dental cones
C) Tablets Administered by Other Routes
• Implantation tablets
• Vaginal tablets
D) Tablets Used to Prepare Solutions
• Effervescent tablets
• Dispensing tablets (DT)
• Hypodermic Tablets (HT)
• Tablet triturates (TT)
 Continued…
Tablets Ingested Orally
• > 90% of current tablets
• Swallowed intact (except chewable tablets)
Compressed Tablets (CT)
• Standard uncoated tablets made by compression using one of the 3
basic methods: wet granulation, dry granulation and direct
compression.
• Usually Compressed
Multiple intended to provide rapid
Tablets disintegration and drug release.
(MCT)
• May be 2- or 3-component system.
• Initial components undergo light pressure; main pressure
is applied on the final component. Layered
• Purpose: Tablet
 Separation of reactive ingredients
(Layered tablet is preferred if complete separation is
intended)
 Repeat-action or prolonged-action Compression
• Shortcoming: dependence on gastric emptying –coated
Tablet
Repeat Action Tablets
Can be designed 
• either as multiple compressed tablets
• or as sugar-coated tablets
(The core tablet for enteric release is coated with shellac or an enteric
polymer and the drug for gastric release is added to the sugar
 Continued…
Delayed-Action and Enteric Coated Tablets
• Delayed-action tablets are intended to release drug after some time
delay or after the passage of the tablet through some part of GIT into
another.
• The enteric coated tablets are a type of delayed-action tablet and is
the most common one.
• They remain intact in the stomach and quickly release in the upper
intestine.
• Materials used for enteric coating:
 Mixed acid functionality and acid ester functionality synthetic or
modified natural polymers, eg, cellulose acetate phthalate,
polyvinyl acetate phthalate and hydroxypropyl methylcellulose
phthalate.
 Being acid esters, insoluble in gastric media (pH up to 4), hydrate
and begin to dissolve when enter the duodenum (pH 4 to 6) and
move further along the small intestine (pH up to 7 to 8)
 Other contributors to breakdown in the intestine: esterases, bile
acids (emulsifier)
• Reasons/Application
 Drugs irritant to gastric mucosa (eg, aspirin, strong electrolytes eg
NH4Cl)
 Drugs causing nausea/ vomiting
 Instability at low pH of the stomach (eg, erythromycin)
 Continued…
Sugar- and Chocolate-Coated Tablets
• Purposes:
 To produce an elegant, glossy, easy-to-swallow dosage form.
 To permit separation of incompatible ingredients between coat and core (eg, in the
preparation of multivitamin and multivitamin mineral combinations).
• Shortcomings:
 Could be easily mistaken by kids for candy.
 Time-consuming operation, need high-skill and greatly increase the bulk
(the problems have been much overcome by modern techniques  such as use of
polymers, automated spray coating and high-drying efficiency side-vented coating
pans)
Film-Coated Tablets
• A thin layer or coat of polymeric material(s) is applied on the tablet surface.
• Earlier the coat was applied from organic solvents, but today aqueous-based systems
are being replaced (due to some disadvantages of organic solvents  what are
they?)
• Can be designed for immediate release (eg, by hydroxypropyl cellulose, hydroxypropyl
methylcellullose) or for slow- or controlled-release (eg, by ethylcellulose)
• Advantages (over sugar-coated tablets) :
 Better mechanical strength (elasticity and flexibility)
 Little increase in tablet weight
 Can retain debossed markings
 Avoids use of sugar
 Continuous/automated operation
 Controlling drug release
 Less likely to be mistaken for candy
• Disadvantages:
 Continued…
Chewable Tablets
• Intended to be chewed in the mouth prior to swallowing and are not to be
swallowed intact (eg, aspirin chewable tablet and antacid chewable tablet).
• Purpose: to provide an unit dosage form for infants, children or elderly who may
have difficulty swallowing a tablet intact.
• Not a good candidate for bitter or foul-tasting drugs.
• Homework: What advantages are offered by the chewable tablet form of
antacids?

Tablets Used in the Oral Cavity

Buccal and Sublingual Tablets
• These two classes of tablets are intended to be held in the mouth  between the
cheek and teeth or in the cheek pouch (buccal tablets) or beneath the tongue
(sublingual tablets)  where they release their drug contents for direct absorption
through the oral mucosa.
• Usually, they are small and somewhat flat.
• The drugs are intended for systemic action and must have a good absorption
through oral mucosa.
• Should be formulated with bland excipients (that do not stimulate salivation) to
minimize swallowing of drug.
• Should be designed not to disintegrate but to dissolve slowly (15-30 min) to
provide for effective absorption.
• Advantages:
 Avoids gastric decomposition (eg, for some steroids and hormones)
 Avoids nauseating effect (eg for methyltestosterone)
 Avoids hepatic first pass effect
 Provides more rapid onset of action (an advantage with vasodilators given by this
 Continued…
Troches and Lozenges
• These tablets forms are intended to exert a local effect in the mouth or
throat  commonly used to treat sore throat or control coughing.
• Drugs incorporated include local anaesthetics, antiseptics and
antibacterials, demulcents, astringents and antitussives.
• Designed not to disintegrate in the mouth but to dissolve or slowly
erode over 30 min or less.
• Lozenges are usually made with a flavoured hard-candy sugar base by
fusion or by a candy-molding process, but can also be made by
compression. On the other hand, troches are made by compression.

Dental Cones
• Relatively minor tablets designed to be placed in the empty socket
remaining following tooth extraction.
• Usual purpose: to prevent bacterial proliferation (by an antibacterial) or
stop/ reduce bleeding (by an astringent or coagulant).
• Should be designed to dissolve or erode slowly in the presence of small
volume of serum or fluid over 20- to 40-min period.
• Usual vehicles: sodium bicarbonate, sodium chloride or an amino acid;
components that may promote bacterial proliferation should be
avoided.
 Continued…
Tablets Administered by Other Routes:
Implantation Tablets
• Implantation or depot tablets are designed for subcutaneous implantation
to provide prolonged drug effects (ranging from one month to a year).
• Usually small, cylindric or rosette-shaped in form and typically not more
than 8 mm in length.
• Administered by a special injector (for rod-shaped tablets) or surgically (for
other shapes)
• Primary application: administration of growth hormones to food-producing
animals (the ear of the animal is typically used  Why?)
Has got little use in humans because of two major safety considerations
involved  What are they?
• Implantation tablets have largely been replaced by other dosage forms,
such as silicone tubes filled with drug or drug-loaded biodegradable
polymers.
Vaginal Tablets
• Vaginal tablets or inserts are designed to undergo slow dissolution and drug
release in the vaginal cavity.
• Typically, ovoid or pear-shaped to facilitate retention in the vagina.
Administered in the upper region of the vaginal tract with some type of
plastic tube inserter.
• Used to release antibacterial agents, antiseptics or astringents for treating
vaginal infections or possibly to release steroids for systemic absorption.
• Often buffered to impart a pH favourable to the action of a given antiseptic
agent.
 Continued…
Tablets Used to Prepare Solutions
Effervescent Tablets:
• Designed to produce a solution rapidly with simultaneous CO2 release.
• Typically prepared by compressing the active ingredient(s) with mixtures of organic
acids (eg, citric or tartaric acid) and sodium bicarbonate.
• These agents undergo a rapid reaction (within 1 min or less) in water producing
CO2 to give a pleasantly flavoured carbonated drink.
• Examples: Saline cathartics, Aspirin (commonest use)
• Advantages:
 Provides a means for extemporaneous preparation of a solution containing
accurate dose.
 Additionally for aspirin: Higher pH of the solution enhance gastric absorption,
Less irritation to gastric mucosa.
• Disadvantage: Unstable (extremely sensitive to moisture) and require special
packaging to protect from moisture.
Dispensing Tablets (DT):
• Intended to produce a solution of a given drug concentration.
• Commonly incorporated materials: silver proteinate, bichloride of mercury,
merbromin and quaternary ammonium compounds.
• All the components must be soluble; the excipients must not produce harmful
effect in the intended application.
• May contain components to provide buffering or isotonicity if the solution is
intended for application to mucous membrane or wound.
• Disadvantages:
 Unavailability of appropriate water on a routine basis for producing sterile
solutions (so, less commonly used than formerly).
 Danger of serious toxic effects if swallowed mistakenly (if the ingredients are
 Continued…
Hypodermic Tablets (HT):
• Consist of one or more drugs with other readily water-soluble
ingredients and are intended to be added to sterile water or water for
injection.
• Advantage: A convenient method for preparing multitude of parenteral
preparations extemporaneously (once widely used).
• Disadvantage: Likelihood of administering a non-sterile solution (so,
little used today).

Tablet Triturates (TT):

• Extemporaneously prepared small, usually cylindric, molded or
compressed tablets.
• Usually incorporate potent drugs mixed with lactose and possibly a
binder (eg, powdered acacia) which are moistened commonly with
alcohol to produce a moldable, compactable mass.
• Rarely seen today because:
• Virtually every drug that would be useful in a tablet dosage form is
available in that form or in capsule form.
• Due to evaporation of alcohol commonly used for moistening the
powder mass,
 these tablets are usually soft and friable &
 drug migration could occur resulting in poor content uniformity.
 Tablet Compression Operation
Stages of Tablet Formation (Compression
Cycle)
 Tablets are made by compressing the tablet
formulation containing a drug or drugs with
excipients (powder/granule) between punches in a
die cavity on a tablet press.
 There are three major stages in the process of
tablet formation:
 Die Filling with powder/granule from the hopper
 Tablet formation by compression of the
powder/granule between the punches in the die
cavity
 Tablet ejection from the die cavity
 Continued…
Tablet Compression Machines (Tablet Presses)
Basic Components of Tablet Compression
Machines
1.Hopper(s)  for holding and feeding granulation
2.Dies  define the size and shape of the tablet
3.Punches  for compressing granulations
4.Cam tracks  for guiding the movement of
punches
5.A feeding mechanism  for moving granulation
from the hopper into the dies
Types of Tablet Presses
6.Single-punch tablet presses
7.Multi-station/ rotary tablet presses
 Continued…
Single-Punch Tablet Presses

Fig. A single-punch tablet

press
(Ref. Aulton)
 Continued…
Compression Cycle of a Single-Punch Tablet
Press
 Continued…
Multi-Station or Rotary Tablet Press
 Continued…
Compression Cycle of a Multi-Station or Rotary Tablet
Press
Physics of Tablet Making  Compaction,
Compression and Consolidation
 The compaction of a powder/ granulation into a
tablet can be regarded to involve two major
physical events:
Compression &
Consolidation
 Compression means a reduction in the bulk
volume of the material as a result of displacement
of the gaseous phase.
 Consolidation is an increase in the mechanical
strength of the material resulting from
particle/particle interactions.
 The compression and consolidation of the two-
phase particle–gas system (powder or granule) due
to the applied force is known as compaction.
 Continued...
Compression:
• Reduction in the bulk
volume of a powder mass
due to compression may
involve a number of
mechanisms:
Repacking
Elastic deformation
Plastic deformation
Brittle fracture
• All the deformation effects
may cause breaking of
bonds and formation of
new bonds between
particles that in turn lead
to consolidation when the
new surfaces are pressed Fig.: Effect of compression on a powder
 Continued...
Consolidation:
Consolidation of the powder bed into a compact
mass may involve two types of bonding:
• Cold welding: Close approximation of particle
surfaces → Development of strong inter-particle
attractive forces
• Fusion bonding: Undissipated frictional heat
generated upon application of the external force →
Melting of contact points of particles → Fusion
Tableting Methods
 Continued…
Direct Compression
 The tablet formulation is directly compressed without
granulation.
 There are few crystalline substances that may be compressed
directly.
Examples: sodium chloride, sodium bromide and potassium
chloride
 Most materials are not directly compressible.
Cause: (i) relatively weak intermolecular attraction
(ii) films of adsorbed gases around.
In addition, the compression of a single substance may produce
non-disintegrating tablet.
→ So, the drug needs to be mixed with a directly compressible
diluent.
 A directly compressible diluent is an inert substance that may be
easily compacted and the compressibility is maintained when
blended with the drug and other tablet ingredients (flow
promoter, disintegrant etc).
 Some examples of directly compressible diluent:
Directly compressible starches eg Sta-Rx 1500
Hydrolysed starches eg Emdex and Celutab
Direct compression grades of sucrose-based diluents such as
 Continued…
Advantages:
 Low labour input
 A dry process
 Fewest processing steps
Disadvantages:
 Not suitable for :
low dose drugs (stratification → poor content
uniformity)
high-dose drugs (large amount of diluent
needed→ excessively big-size tablet)
 Drug-diluent reaction  in some instances (eg,
amine compounds + spray dried lactose  yellow
discoloration)
 Static charge build-up on drugs during mixing/
screening due to the dry nature ( → non-uniform
distribution of drug in the granulation.)
 Continued…
Dry Granulation (Compression Granulation)
 The formulation is compressed into large compacted
masses (slugs), which are then milled and/or screened
into granules and finally compressed into tablets.
 When a single slugging process is not enough to confer
the desired granular properties, the process is repeated
before final compression.
Application/ Advantages:
 A valuable technique for situations where:
 the effective doses of drugs are too high for direct
compaction
the drug is sensitive to heat, moisture, or both 
which precludes wet granulation.
 Requires less equipment and space than wet
granulation method.
Examples:
Many aspirin and vitamin formulations.
 Continued…
Roller Compactors
 A specially designed
machine for large scale
compression
 granulation.
Can produce as much
as 500 kg per hour or
more of compacted
ribbon-like material.
Advantages (over
slugging)
Increased production
capacity
Greater control over
compaction pressure
and dwell time
No need for excessive
lubrication of the
powder.
 Continued…
Wet Granulation
 In wet granulation, the granules are formed by binding
the powders together with an adhesive, instead of by
compaction.
 The technique uses the same preparatory and finishing
steps as the other two techniques.
The unique part is the granulation process that involves
:
 wet massing of the powder
 wet screening/sizing/milling
 drying.
Wet massing:
 In this step, the adhesive is added to the powder
mixture in a solution, suspension or slurry and mixed
together to form a moist mass.
 The binder may also be added dry into the powder mix
 Continued…
 The method of binder incorporation largely depends on the
volume of liquid required to make the powder mass merely
moist rather than wet or pasty.
 When only a small quantity is needed, the binder is
blended in dry;
 when a large quantity is required, the binder is usually
added in liquid.
 Solubility of the binder also influences the choice  the
solution should be fluid enough to disperse readily in the
powder mass.
 The granulating liquid plays a key role in the granulation
process:
¾ Liquid bridges develop between particles.
¾ The surface tension forces and capillary pressure of the
liquid are primarily responsible for initial granule formation
and strength.
 As the powder mass is mixed with the granulating fluid to
attain a uniform dispersion and activate the binder, the
 Continued…
Wet screening/sizing/milling:
 The moist mass is converted into coarse, granular
aggregates by wet screening.
 This process further consolidates granules and
increases particle contact points.
Drying:
 Finally, granules are dried.
 During drying, fusion or recrystallization of particles and
curing of the binding agent produce interparticulate
bonds.
Here, the van der Waals forces play a significant role.
Assignment:
1) What are the problems associated with the use of
volatile or inflammable solvents for wet granulation?
2) Make a list of tablet products (by generic name of the
drug) manufactured by direct compression or dry
 Flow Characteristics of Granules
Importance of flowability:
Free-flowing powders enable:
• uniform blends
• continuous and reproducible material discharge from the
hopper into the die
• the possibility of in-die rearrangement during tableting.
Factors affecting granule/powder flow
• Shape: Particles with spherical shape flow better.
 Spherical shape  Minimum contact (between particles and
with the wall of the machine parts)  cohesion +  friction +
tendency of mechanical interlocking   flow
 Irregular shape   contact points  cohesion + friction +
tendency of mechanical interlocking   flow
• Size and Size Distribution: Particles with larger size and
narrow size distribution flow better.
  Size   surface area-to-volume ratio   points of contact
  cohesion +  friction   flow
 Continued…
In general: > 250 µm  free-flow,
< 100 µm  reduced flow
< 10 µm  poor flow
 Particle size enlargement, through granulation, is commonly
used to decrease the influence of the cohesive forces, and
thus improve the flowability of powders
 Wide size distribution  smaller particles fill in the voids
between larger ones  more efficient particle packing 
 cohesion and mechanical interlocking   flow
• Surface roughness:
Rough surface   contact points  cohesion + friction +
tendency of mechanical interlocking   flow
• Density:
 density  tight packing of particles (low porosity of the
powder bed)  free-flowing powder
• Moisture:
Moisture in the granule bed  Forms liquid bridge between
particles   inter-particle cohesion and friction   flow
 Continued…
Bulk density:
• ‘Bulk density’ is a measure used to describe a packing of
particles or granules.
• The bulk density (ρb) of a powder is its mass divided by the
volume occupied by the powder. That is:
M
b 
Vb
where: M  mass of the particles
Vb  total volume of packing
Measurement:
• Pour gently an weighted sample of powder or granulation to
a graduated cylinder through a funnel. Note the initial
volume.
• Tap the sample manually or mechanically until no further
reduction in volume occurs. Note the final volume.
Untapped/ loose/ aerated bulk density (ρu): Bulk density
corresponding to the initial volume. [This is often referred to
simply as ‘bulk density’.]
Tapped (bulk) density (ρ ): Bulk density corresponding to
Continued…

Mechanical
 Continued…
Assessment of Flowability
(a) Angle of Repose ()
(b) Carr’s index/ Compressibility index (CI) and Hausner ratio (HR)
(c) Hopper flow rate
Angle of Repose ()
• When a granular material is poured onto a horizontal surface, it
forms a conical pile. The maximum angle possible between a
loosely piled conical heap of powder and the horizontal plane is
known as the angle of repose ().
• It is a measurement of the frictional and cohesive forces.
frictional and cohesive forces  resistance to flow   angle of
repose
•   30  free-flowing;   40  poorly flowing
Methods of measurement:
a)Fixed height cone method
Static angle
b)Fixed base cone method
of repose
c)Tilting box method
d)Revolving cylinder/rotating drum
method
(Dynamic or kincetic
1 H where angle
H: of repose)
height of cone
 tan
R R: radius of cone
 Continued…
Carr’s Index or Compressibility Index (CI) and
Hausner Ratio (HR)
t  u CI  flow
CI  100
t CI > 20%  poor flow
t HR < 1.25 
HR 
u free flowing
HR > 1.4  poor flow
Hopper Flow Rate
• Monitor continually the flow of material out of conical hopper
onto a recording balance device.

Fig.: Conveyor system for illustrating solid-flow measurement

• The method is quite simple and the results are easy to
interpret.
Processing Problems
· Capping and Lamination
· Picking and Sticking
· Mottling
· Weight Variation
· Hardness Variation
· Double Impression
Source of the problems could be:
 Formulation
 Tablet Press
 Combination of both.
Capping and Lamination:
· Capping: Partial or complete separation of the top or
bottom crowns of a tablet from the main body.
· Lamination: Separation of a tablet into two or more distinct
layers.
 Cause Remedy
· Air entrapment into the particles/
granules during compression
(not supported by research)
· Inadequate stress relaxation · Precompression
· Slowing down tabletting rate
· Reducing the final compression pressure
· Deep concave punches Use flat punch
 inconsistent expansion of the crown
and body during decompression
 Concave or beveled edge punch faces
gradually curve inward → “claw”
formation & unequal pressure on the
centre and edges of the tablet.
· Development of wear “ring” in die in Turn over the die, Regulate the depth of
the area of compression punch penetration, Use dies with tungsten
carbide insert
· Incorrect set-up of the lower punch Correct the set-up
or the sweep-off blade
· Insufficient moisture in granulation Add a hygroscopic substance (eg, sorbitol,
methylcellulose, polyethylene glycol 4000) for
moisture-critical granulations
Picking and Sticking:
· Picking: The surface material removed by a punch from a tablet
“sticking” to it.
· Sticking: Tablet material adhering to the die wall.
It may cause:
o chipping of tablet edge or rough edge
o damage to the lower punch head and /or linked cam track,
o build of materials on the punch faces

Cause Remedy
• Engraving / • Design lettering as large as possible
Embossing on • Reformulate the tablet to a larger size
punch tips • Chromium plating of the punch face
• Adding colloidal silica to the formulation (as a polishing agent)
• Additional binder or change in binder (→ less adherent granulation)
• Low-melting-point • Dilute the active ingredient with additional higher-melting-point
active ingredient/ materials and consequent increase in tablet size
excipients eg, stearic • Reduce low-melting-point lubricants/
acid/PEG ) Substitute with higher-melting-point replacements
• Refrigeration of the granulation and tablet press
• High moisture level • Further drying of granulation
Mottling:
Unequal distribution of color on a tablet (with light and dark areas in an otherwise
uniform surface).

Cause Remedy
• Difference in drug and excipient color Use colorant/dye
• Colored degradation product of the drug

• Migration of dye to the granulation • Change solvent system

surface during drying • Change the binder system
• Reduce the drying temperature
• Grind to a smaller particle size
• Non-uniform dispersion or too large • Take corresponding corrective measures
particle size of the dye in direct
compression formulation
• Colored adhesive gel solutions (needs to • Further wetting/overwetting (may increase DT)
be added hot and precipitates out in • Add fine powder adhesives eg acacia &
contact with much cooler powder tragacanth before granulating fluid
mixture) → non-uniform distribution of • Disperse a dry color additive during blending
the color
Weight Variation
· Tablet weight depends on: the amount of granulation in the die.
· So, anything that affects die filling causes weight variation.

Causes Remedy
(Factors affecting die filling)
Granule Size and Size Distribution Smaller granule size
 Granule size:
Large granules for a small die  High percentage
weight variation with the difference of just a few
granules
Granule size distribution:
Narrow size distribution
Wide size distribution  Small granules fill in the
gaps between large granules in the die  Same
apparent volume, but different weight of fill 
Larger weight variation
Poor flow
 Poor granulation flow from Hopper  Granulation
· Add/ increase glidant, eg talcum,
moves spasmodically through the feed frame 
colloidal silica
Some dies are incompletely filled · Use induced die feeders
 Machine speed in excess of the granulation’s
flow capabilities  dies are not filled properly
 Poor flow out of hopper due to arching/ bridging · Attach vibrators to hopper sides
or rat holing
 Poor flow due to poor hopper design · Take corresponding measure
 Surges of excessive flow · Restrict flow out of the hopper
· Specially designed feed frame
Causes Remedy
(Factors affecting die filling)
Poor Mixing: Take corresponding measure
Inadequate mixing of glidants and lubricants
 Unsatisfactory granulation flow from the
hopper into the die

Punch Variation  Difference in die fill Need a good punch and die
control program

Hardness Variation
· Hardness depends on the weight of material and the space between
the upper and lower punches at the moment of compression.
· So, hardness variation comes from the same causes as weight
variation, viz.:
 Differences in die fill
 Variation in the distance between punches

Double Impression
Cause:Engraving in the lower or upper punch with possible rotation of
the lower punch when it freely falls down or of the upper punch between
pre-compression and final compression (if the machine uses double
compression)
 EVALUATION OF TABLET
Quantitative evaluations of tablet’s physical, chemical and
bioavailability properties are essential for 
a) Designing tablets
b) Monitoring tablet’s production quality
General • Thickness
Appearance • Identification
markings
Evaluatio • Organoleptic
properties
n of • Weight variation
• Hardness &
& Friability
Content uniformity
Tablets Drug content • Disintegration
& Release • Dissolution
GENERAL APPEARANCE
The general appearance of a table, its visual identity and
overall elegance is essential for:
• consumer acceptance
• control of lot-to-lot uniformity and general tablet-to-tablet
uniformity &
• monitoring trouble-free manufacturing.
 Continued…
Thickness
Pharmaceutical implications:
• Thickness variation can affect:
(a) Consumer acceptance, (b) Unit dose packaging & (c) Fill
level in
a container
• The thickness variation should be controlled within 5% of a
standard value.

Factors that can influence the thickness:

(a) Compressive load, (b)Die fill & (c) Particle size distribution
and
packing

Measurement techniques

Micromete Slide
 Continued…
Identification Markings
• The identification markings placed on the tablet should be
clearly legible and elegant.
• These are placed in form of: (a) embossing, (b) engraving or
(c) printing.
• Usually include: (a) the company name or symbol, (b) a
product code, (c) the product name or (d) the potency.
Organoleptic Properties
Colour:
Pharmaceutical importance:
• Colour provides a means of rapid identification and aesthetic
elegance for consumer acceptance.
• Non-uniformity of colour (mottling) reduces aesthetic appeal
and may give the consumer an impression of non-uniformity
of content and general poor quality.
Assessment:
(a) visually against a standard (b) instrumentally by
reflectance spectrophotometry, tristimulus colorimetry or
microreflectance photometry.
Limitation of visual comparison: lack of precision and
subjective variation.
Odour
Continued…
Pharmaceutical importance
• Odour may be indicative of a stability problem (eg, odour of acetic
acid in degrading aspirin tablets).
• In some cases, the odour present may be the characteristic of the
drug, excipients or the dosage form.
Taste
Pharmaceutical importance
Important in consumer acceptance of chewable tablets.
Assessment:
• Many companies utilize taste panels to judge the preference of
different flavours and flavour level.
• However, due to subjectiveness of taste preference, the control of
taste in the production of chewable tablets is often simply the
presence or absence of a specified taste.
Surface characteristics:
• The level of surface flaws such as chips, cracks, foreign
contaminants (eg, hair, oil drops, and dirt), surface texture
(smooth vs. rough) and appearance (shiny vs dull) may have a
zero-defect specification.
Assessment:
• Visual inspection. Subjective in nature.
• Electronic devices (in development) hold promise for making
 Continued…
Hardness and Friability
Hardness
• Hardness is the force required to break a tablet in a
diametric compression test.
• Sometimes it is also referred to as the ‘crushing strength’.

Pharmaceutical importance:
• Tablets require a certain amount of hardness and resistance
to friability to withstand mechanical shocks of handling in
manufacture, packaging, shipping and in the hands of the
consumer.
• Adequate tablet hardness and resistance to friability are
necessary requisites for consumer acceptance.
• Excessive hardness can affect tablet disintegration , and
perhaps more significantly, the drug dissolution .
This is especially important for drug products that possess
real or potential bioavailability problems or may show altered
dissolution profiles as function of the compressive force.
 Continued…
Process variables affecting tablet hardness:
• Compression force: At a constant die fill, compression force
 hardness.
• Die fill: At a constant compression force, die fill  hardness
• Time elapsed after compression: Tablets are harder several
hours after compression than they are immediately after
compression.
• Lubricants: concentration or mixing time hardness
• Tablet size: size hardness
• Punch shape: For a given tool, flat bevelled tool produce a
tablet harder than a deep cup tool.
Measurement:
• By diametric compression test:
The tablet is placed between two anvils, force is applied to
the anvils, and the crushing strength that just causes the
tablet to break is recorded.
• Devices used:
a) Monsanto tester
b) Strong-Cobb tester
c) Pfizer tester
d) Erweka tester
 Continued…

Erweka Tester

Monsanto Tester
Pfizer Tester

Schleuniger Tester
Strong-Cobb Tester
Assignment: The operation and merits/
demerits (if any) of different hardness
 Continued…
Friability:
Definition and Pharmaceutical Importance:
• Tablet hardness is not an absolute indicator of a tablet’s strength
because some formulations, when compressed into very hard
tablets, tend to “cap” on attrition (losing their crown portions).
• Friability is a complementary measure of tablet’s strength that
measures a tablet’s tendency to powder, chip and cap/fragment
when handled.
• Firable tablets lack elegance and consumer acceptance, and can
produce an excess of dust during coating and packaging.
• Fribility can also produce higher weight variation or content
uniformity.
Measurement:
• A set of preweighed tablets are subjected to
combined effects of abrasion and shock in a
plastic chamber.
• The chamber is revolved 100 times (4 min @
25 rpm) and then the tablets are dusted and
reweighed.
• For conventional compressed tablets, a
weight loss of < 0.5-1.0% is considered Roche Friabilator
acceptable.
 Continued…
Conditions giving high friability
• Some chewable and most effervescent tablets (special
stack packaging is required)
• Use of concave (specially deep concave) punches 
specially punches in poor condition or worn at surface
edges (cause whiskering)
• Use of very dry granulation with only fractional % of
moisture (More friable than granulation containing 2-4%
moisture)
Capping on Friability Testing
Should not be considered for commercial use
( regardless of % loss)
Rough Handling Test
• Can give an indication of how well a tablet will hold up
in its specified package and shipping container during
shipment.
• Usually include a vibration test, a drop test, and an
inclined plane impact test.
 Continued…
DRUG CONTENT & RELEASE
• Evaluation of the drug content of a tablet and its ability to
release the drug is necessary to ascertain its potential for
efficacy.
Weight Variation and Uniformity of Content
• Four tests are routinely performed to evaluate drug content
of a tablet and tablet-to-tablet uniformity of content:
 Determination of average weight
 Weight variation test
 Analysis of potency
 Content uniformity test
Determination of average weight
• Average weight determination is routinely performed
throughout the compression process on composite samples
of tablets (usually 10).
Weight variation test
• Within the composite sample that has an acceptable average
weight, there could be tablets excessively overweight or
underweight.
Therefore, a weight variation test needs to be performed.
 Continued…
• The USP weight variation test is run on a sample of 20
tablets. The tablets meet the test if no more than 2 tablets
are outside the permissible percentage limit and none
beyond 2 times the percentage limit.
• The weight variation test could reflect the uniformity of
content if all or essentially all (90-95%) of the tablet were
active ingredient (eg aspirin tab) or if the uniformity of the
drug distribution in the granulation were perfect.
• The test is clearly not sufficient to assure uniform potency of
tablets of low- or moderate-dose drugs.
Analysis of potency
• In potency determination, a composite sample of the tablets
is ground up, mixed and analysed to produce an average
potency.
• For highly potent, low-dose drugs (eg, digoxin) the
acceptable potency range is usually not less than 90% and
not more than 110% (ie, 10%) of the labelled amount.
• For most other larger-dose drugs the permitted official
potency range is not less than 95% and not more than 105%
(ie, 5%) of the labelled amount.
 Continued…
Content Uniformity Test
• The average assay result could mask a wide variation in
potency which could be dangerous in case of low-dose
potent drugs with a narrow therapeutic window/range.
• Therefore, to assure uniform potency for tablets of low-dose
drugs, a content uniformity test is applied.
• In this test, 30 tablets are randomly selected for the sample,
and at least 10 of them are assayed individually.
Nine of the 10 tablets must contain not less than 85% or
more than 115% (ie, 15%) of the labelled content.
The 10th tablet may not contain less than 75% or more than
125% (ie, 25%) of the labelled content.
• If these conditions are not met, the remaining 20 tablets
must be assayed individually and none of them may fall
outside 85-115% (ie, 15%) range.
Factors causing nonuniformity of content
• Nonuniform distribution of the drug substance throughout
the powder mix or the granulation
• Segregation of the powder mixture or granulation
• Tablet weight variation.
Disintegration
Continued…
Significance:
• For most tablets, disintegration into smaller particles or granules is
the first important step for appearance of a drug into solution.
• Since the dissolution of a drug from the fragmented tablet controls
partially or completely the appearance of a drug into blood,
disintegration serves:
 as a guide to formulator in the preparation of a optimum tablet
formula
 as an in-process
Measurement of disintegration time (DT)
control test to ensure lot-to-lot uniformity.
• USP disintegration device is used for measuring the
DT of a Tablet.
• To be compliance with the USP standards, the
tablets must disintegrate and all particles must
pass through the 10-mesh screen in the time
specified.
If any residue remains, it must have a soft mass
with no probably firm core.
Disintegration time:
• Uncoated tablets: Minimum - 5 min (aspirin tablets);
Maximum -30 min (majority).
• Enteric coated tablets: No disintegration after 1
USP Disintegration
hour in simulated gastric fluid; then should Tester
disintegrate in 2 hours plus the time specified in the
 Continued…
Dissolution
Significance:
• To ascertain that the drug is released from disintegrated
particles in solution at an appropriate rate.
• The rate of dissolution can directly indicate the efficacy of a
tablet product as well as the bioavailability differences
between formulations.
Assessment of Dissolution Rate
• In vivo bioavailability measurements
• In vitro dissolution tests
In vivo bioavailability measurement
Merit: Allows most direct assessment of drug release.
Demerits: Restricted for several reasons:
• length of time needed to plan, conduct and interpret the
study
• highly skilled personnel required for human studies
• low precision and high variability typical of the
measurements
• high cost of studies
• use of human subjects for “nonessential” research &
• necessary assumption that a perfect correlation exists
 Continued…
In vitro dissolution studies
Scope:
• Because of the practical limitations of in vivo bioavailability
studies, in vitro dissolution studies are widely used as an
indirect measurement of bioavailability, especially in
preliminary assessment of formulation factors and
manufacturing methods that are likely to influence
bioavailability.
• However, it is critically important to correlate the in vitro
dissolution tests to in vivo bioavailability tests.
Objectives:
1)To ensure that the drug release is as close as possible to
100% &
2)To show that the release rate is
• uniform batch to batch &
• equal to the batches proven bioavailable and clinically
effective.
Methods: Continued…
USP-NF suggests two apparatuses for determining dissolution
rates:

Shaft
Shaft
Paddl
e
Baske Blad
t e
Tablet
Wire helix 375C
375C 100-mLFlask Tablet
Apparatus Apparatus
100-mLFlask 2
1
USP/NF monograph of a product specifies:
●test medium and volume, ●apparatus to be used, ●speed
(rpm) of
rotation, ●time limit of test, and ●assay procedure.
 Continued…
Interpretation of Result:
• Dissolution testing and interpretation can be continued
through three stages if necessary.
• In stage 1 (S1), 6 tablets are tested and are acceptable if all
of the tablets are (Q + 5%) [Q  monograph tolerance
• If the tablets fail S1, an additional 6 tablets are tested
limit].
(S2).
The tablets are acceptable if the average of the 12 tablets is
≥ Q and no unit is < (Q - 15%).
• If the tablets still fail the test, an additional 12 tablets
are tested (S3).
The tablets are acceptable if the average of all 24 tablets is ≥
Q and if not more than 2 tablets are < (Q - 15%).
• Industrial pharmacists routinely test their formulations for
dissolution. The results are plotted as concentration versus
time and values for t50%, t90% and the % dissolved in 30 min are
used as guides.
• A value for t90% of 30 min is often considered satisfactory and
Since: a common dissolution tolerance in the USP/NF is 75%
is an excellent
dissolved in 45 goal.
min.
 Read Yourself
• Properties of Tablet
• In-Process Quality Control
 Reference Books

1.The Theory and Practice of Industrial

Pharmacy – by Lachman et al.
2.Ansel’s Pharmaceutical Dosage Forms and
Drug Delivery Systems
3.Aulton’s Pharmaceutics
4.Remington: The Science and Practice of
Pharmacy
SPARE SLIDES
 Continued…
Roller Compactor is a specially designed machine for large scale
compression granulation.
 Roller compactors can produce as much as 500 kg per hour or more of
compacted ribbon-like material, which can then be screened or milled
into a granulation.
Operating Principle:
 Roller compactors utilize two rollers that revolve towards each other.
 By means of a hydraulic ram, one of the rollers is forced against the
other, to exert a known fixed pressure on the powdered material
flowing between rollers.
 Powdered material is fed between the rollers by a screw conveyor
system.
On most modern compactors, the feed screws consist of a variable-
speed horizontal and vertical screw.
The horizontal screw picks up the powder from the hopper and
maintains a continuous flow to the vertical screw.
The vertical screw delivers the powder to the compaction rolls.
 After passing through the rollers, the compacted mass comes out as a
thin wide ribbon that falls apart into large segments. These are
equivalent to the slugs produced by the slugging process.
 The segments are then screened or milled for the production of
granules.
Advantages (over the slugging process)
Increased production capacity