Transcript Tablets - Faculty of Pharmaceutical Sciences, KKU

Tablets
Assoc. Prof. Dr. Jomjai Peerapattana
Faculty of Pharmaceutical Sciences
Khon Kaen University
Scope
Introduction
Advantages and disadvantages of
compressed tablets
Types of tablets
Tablet compression machine
Tableting methods
– Direct compression
Introduction
1843 a patent was granted to Thomas
Brockedon (Englishman) for manufacturing
pills and lozenges
1874 both rotary and eccentric presses
1885 glyceryl trinitrate tablets was in the BP
No other tablet monograph appeared until 1945
1980 nearly 300 monographs for tablets
Advantages
Production aspect
– Large scale production at lowest cost
– Easiest and cheapest to package and ship
– High stability
User aspect (doctor, pharmacist, patient)
– Easy to handling
– Lightest and most compact
– Greatest dose precision & least content variability
– Coating can mark unpleasant tastes & improve pt.
acceptability
Disadvantages
Some drugs resist compression into dense compacts
Drugs with poor wetting, slow dissolution,
intermediate to large dosages may be difficult or
impossible to formulate and manufacture as a tablet
that provide adequate or full drug bioavailability
Bitter taste drugs, drugs with an objectionable odor,
or sensitive to oxygen or moisture may require
encapsulation or entrapment prior to compression or
the tablets may require coating
Absorption of
drug form
tablets
Ingredients used in tablet formulations
Drugs
Fillers, diluent, bulking agent
– To make a reasonably sized tablet
Binders
– To bind powders together in the wet granulation
process
– To bind granule together during compression
Disintegrants
– To promote breakup of the tablets
– To promote rapid release of the drug
Lubricants
– To reduce the friction during tablet ejection between
the walls of the tablet and the walls of the die cavity
Glidants
– Reducing friction between the particles
– To improve the flow properties of the granulations
Antiadherants
– To prevent adherence of the granules to the punch faces
and dies
Dissolution (enhancers and retardants)
Wetting agents
Antioxidants
Preservatives
Coloring agents
Flavoring agents
Essential properties of tablets
Accurate dosage of medicament, uniform in weight,
appearance and diameter
Have the strength to withstand the rigors of
mechanical shocks encountered in its production,
packaging, shipping and dispensing
Release the medicinal agents in the body in a
predictable and reproducible manner
Elegant product, acceptable size and shape
Chemical and physical stabilities
Types of tablets
Route of administration
– Oral tablets
– Sublingual or buccal tablets
– Vaginal tablets
Production process
– Compressed tablets
– Multiple compressed tablets
 Tablet within a tablets: core and shell
 Multilayer tablet
– Sugar coated tablets
Protect tablets from moisture
Mask odor and flavor
Elegance
– Film coated tablets
Thin film coat
Soluble or insoluble polymer film
– Chewable tablets
Rapid disintegrate
Antacid, flatulance: rapid action
Children drug
– Effervescent tablets
Dissolve in the water before drink
Tablet production
Powders intended for compression into tablets
must possess two essential properties
– Powder fluidity
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
Tableting procedure
Filling
Compression
Ejection
Tablet compression machines
Hopper for holding and feeding granulation to be
compressed
Dies that define the size and shape of the tablet
Punches for compressing the granulation within the dies
Cam tracks for guiding the movement of the punches
Feeding mechanisms for moving granulation from the
hopper into the dies
Single punch machine
The compression is applied by the upper punch
Stamping press
Single Punch
Machine (Tablets)
Upper and
Lower Collar
Collar locker
Multi-station rotary presses
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 an lower turrets
The portion holding the dies is called the die table
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 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
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
Tableting methods
Dry methods
– Direct compression
– Dry granulation
Wet methods
– Wet granulation
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
Advantages
– Economy
Machine: fewer manufacturing steps and
pieces of equipment
Labor: reduce labor costs
Less process vallidation
Lower consumption of power

– Elimination of granulation process
Heat (wet granulation)
Moisture (wet granulation)
High pressure (dry granulation)
Processing without the need for moisture and
heat which is inherent in most wet granulation
procedures

Avoidance of high compaction pressures involves
in producing tablets by slugging or roll
compaction
– Elimination of variabilities in wet granulation
processing

Binders (temp, viscous, age)
Viscosity of the granulating solution (depend on
its temp),
 How long it has been prepared,

Rate of binder addition and kneading can affect
the properties of the granules formed
 The granulating solution, the type and length of
mixing and the method and rate of wet and dry
screening can change the density and particle size
of the granules, which can have a major effect on
fill weight and compaction qualities


Type and rate of drying

can lead not only to critical changes in equilibrium
MC but also to unblending as soluble active
ingredients migrate to the surfaces of the drying
granules
More unit processes are incorporated in
production, the chances of batch-to-batch
variation are compounded
– Prime particle dissociation
Each primary drug particle is liberated
from the tablet mass and is available for
dissolution
Disintegrate rapidly to the primary
particle state

– Uniformity of particle size
– Greater stability of tablet on aging
Color
Dissolution rate
Fewer chemical stability problems would be
encountered as compared to those made by
the wet granulation process

Concerns
– Excipient available from only one supplier
and often cost more than filler used in
granulation
– Procedure conservation
– Machine investments
– Lack of material knowledge
– Physical limitation of drug
No compressibility
No flowability

– Physical characteristics of materials (both
drug and excipient)
Size and size distribution
Moisture
Shape and surface

Flowability
Density

– Lot to lot variability
– Dusting problem
– Coloring
Direct compression fillers
Common materials that have been modified in
the chemical manufacturing process to improve
fluidity and compressibility
Lactose
Soluble fillers
– 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
Loss compressibility upon initial compaction
Problem of browning due to contamination of
5-hydroxyfurfural which was accelerated in
the presence of basic amine drugs and
catalyzed by tartrate, citrate and acetate ions

– Fast-Flo lactose (early 1970s)
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

– Anhydrous lactose: free flowing crystalline lactose
Produced by crystallization above 93C which
produces the beta form
Pass through steam heated rollers
Good flow property, contained high amount
of fines, its fluidity is less than optimal
Can be reworked
At high RH anhydrous lactose will pick up
moisture forming the hydrated compound 
increase in the size of tablets if the excipient
makes up a large portion of the total tablet
weight
Excellent dissolution property

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

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
Dextrose
– Emdex: spray crystallized
90-92% dextrose, 3-5% maltose and the
remainder higher glucose polysaccharides
Available both anhydrous and a hydrate
product
Excellent compressibility
Largest particle size, blending problem may
occur
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%
Mannitol
– Exists in a number of polymorphic forms
– Not make as hard a tablet as sorbitol
– 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
Maltodextrin
– Maltrin
Highly compressible
Completely soluble
Very low hygroscopic
Starch
Insoluble fillers
– Starch 1500: intact starch grains and ruptured
starch grains that have been partially hydrolyzed
and subsequently aggromerated
Extremely high MC (12-13%)
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
– Deforms elastically when a compression force is
applied, it imparts little strength to compacts
– Lubricants tend to dramatically soften tablets
containing high concentrations of Starch 1500

– Spray dried starch
Era-Tab: spray-dried rice starch
Good fluidity
 MC 10-13%
 Compressibility depend on moisture
 Reworkability
 Low bulk density

Celulose
– 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
PH102 more agglomerated, larger particle size,
slightly better fluidity but not significant
decrease in compressibility
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 fillerbinder-disintegrant, rapid passage of water into
the compact and the instantaneous rupture of
hydrogen bonds

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
Nonhygroscopic 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

References
ยาเม็ด (ม.มหิ ดล)
Pharmaceutics. The science of dosage forms design.
(M.E. Aulton)
The theory and practice of industrial pharmacy.
Pharmaceutical dosage forms : Tablets. Volume 2.
Pharmaceutical dosage forms and drug delivery
systems.