Tablets

Introduction
 Oral route is widely employed route for treatment

 90% of all drugs are administered orally for systemic action

 Among orally administered drugs solid dosage forms represent

the preferred class

 Unit dosage form: The dosage form which deliver one single
unit of dosage of the drug (Tablets and capsules)

 “Tablets are solid, flat or biconvex dishes, unit dosage form,

prepared by compressing a drug or a mixture of drugs, with or
without diluents.”

 Dose accurately placed hence less errors

 Advantages
 Unit dosage form offer greatest capabilities of all oral
dosage forms for dose precision and least content variation

 Lowest cost among all oral dosage forms

 Lightest and most compact

 Easiest and cheapest to pack and ship

 Product identification is most simplest and cheapest

 Ease of swallowing

 Better suited for large sale production

 Chemical, mechanical and microbiological stability

 Disadvantages
 Some drugs resist compression: flocculent, amorphous or
low density

 Drugs with poor wetting, intermediate to large dose,

optimum absorption high in gastrointestinal tract can not be
formulated as tablet

 Bitter tasting drugs, with objectionable odor, or drugs

which are sensitive to oxygen or atmospheric
moisture may require encapsulation or entrapment prior to
compression.
 Ideal Characteristics of Tablets
 Elegant product having its own identity while being free of
defects like chips, cracks, discoloration, and contamination.

 Sufficient strength to withstand rigors of mechanical

shock and agitation encountered during production,
packaging, shipping and dispensing.

 Chemical stability: shelf life

 Physical stability: color, physical integrity like shape etc.

 Release the drug in desired and reproducible manner.

 Types and classes of tablets
 Oral tablets for ingestion

◦ Compressed tablets

◦ Multiple compressed tablets

 Layered tablets

 Compression coated tablets

◦ Repeat action tablets

◦ Delayed action and enteric coated tablets

◦ Sugar and chocolate coated tablets/Film coated tablets

◦ Chewable tablets
 Tablets used in oral cavity

◦ Buccal and Sublingual tablets

◦ Trouches and lozenges

◦ Dental cones

 Tablets administered by other routes

◦ Implantation tablets

◦ Vaginal tablets

 Tablets used to prepare solutions

◦ Effervescent tablets

◦ Dispensing tablets (DT)

◦ Hypodermic tablets (HT)

◦ Tablet triturates (TT)

Excipients
 Conventional tablets contain same classes of components in
addition of the active constituents:

◦ Diluents

◦ Binder or adhesive

◦ Disintegrant

◦ Lubricant

 Some tablets may contain flow promoters

 Others optional colorants, flavors, sweeteners

 Diluents
 Fillers designed to make bulk of the tablets when the drug
dosage is inadequate
 Criteria:
◦ Nontoxic and acceptable by regulatory authorities of
countries where the tablet has to be marketed
◦ Commercially available in acceptable grade
◦ Cost must be acceptably low
◦ Physiologically inert
◦ Physically and chemically stable
◦ Free from microbial load
◦ Color compatible
◦ No deleterious effect on bioavailability of drug
 E.g. Lactose, Dicalciun phosphate, starch, dextrose,
sorbitol, Sucrose, Mannitol (chewable tablet, freely
soluble in water, cool taste), Microcrystaline Cellulose
(excellent compression property, highly stable and
disintegrating property).

 Excipient reduced bioavailability:Tetracycline form

complex with calcium based diluent (di calcium phosphate,
DCP)

 Chemically incompatible: Interaction of amine drugs

with commonly used diluent, Lactose in presence of
metal stearate lubricant resulting in discoloration of tablets
Binders or adhesives
 Binder is added in liquid or dry form to form granules or to
form cohesive compacts for direct compression.

 e.g. Aacacia, tragacanth, Glucose, Gelatin, providone (PVP),

Starch mucilage

Disintegrants
 Added to facilitate the breakdown of tablets when it
comes in contact of water in GIT.

 E.g. clays, starch, crospovidone, croscarmellose sodium,

sodium starch glycolate
 Lubricants, antiadherants and glidants
 Lubricants are intended to reduce friction during tablet
ejection between walls of tablet and walls of die cavity.
E.g. Calcium and magnesium stearates, Talc, polyethylene
glycols

 Antiadherants reduce sticking or adhesion of any of the

granules or powder to the faces of punches and or to the die
wall. [Link], magnesium stearates and starch

 Glidants are intended to promote flow of the tablet

granulation or powder materials by reducing friction between
the [Link], corn starch and colloidal silica
 Colors, flavors and sweeteners
 Serves three purposes:

◦ Disguising of off-colored drugs

◦ Product identification

◦ Production of more elegant product

 Two forms of dyes: FD&C and D&C

 lake forms are adsorbed on hydrous oxides and applied as

dry powders

 Flavor oils are added to tablet formulations

 Sweeteners: Sucrose, saccharin, aspartame

Methods of tablet preparation
 Direct compression

 Granulation methods

◦ Wet granulation

◦ Dry granulation

 Tablet is the most complex Dosage form. The tablet

manufacturing is an art as well as a science. It consists of
the two important steps:

◦ Step1: Blending of drug with excipients (mixing and

granulating) and;

◦ Step 2: compression (by punches onto die cavity)

Direct compression
 Few crystalline substances can be granulated directly e.g.
sodium chloride, sodium bromide and potassium chloride
 If disintegration is a problem other substances are
needed which in turn interfere with compressibility
 Most large dose drugs do not lend themselves for this
process
 However, use of compressible diluents with moderately
dose drugs can be utilized
 Direct compressible diluent must possess good flow and
compressibility, should be inert, tasteless,
inexpensive, able to disintegrate
 Limitations
◦ Differences in density of drug and diluents may cause
stratification within the tablet

◦ Large dose drugs posses problems

◦ Direct compressible diluent can interact with drug. e.g.

spray dried lactose causes yellow discoloration of amine
compounds

◦ Static charge build up can occur due to the dry nature

of direct compression

 Steps in preparation: screening or milling and mixing

 Dry granulation
 Steps involved:

◦ Slugging/Compaction of tablet
components by means of a
press (slugs)

◦ Milling

◦ Screening

◦ Final compression

 Slugging can be done once or

more times: Impart strength to
the tablet and increases
flowablity Roller compacter
Wet granulation
 Granules formed by binding drug with the help of binder
or adhesive

 Solution, suspension or slurry containing binder is added

to the tablet powder. Binder can be added in dry state also

 Method of addition of binder depends upon solubility of

materials and the mass should be merely moist rather
than wet or pasty

 Wet screening: conversion of moist mass into coarse

granular aggregates by passing hammer mill or oscillating
granulator
 Drying: inter-particle bonds results due to fusion and re-
crystallization

 Dry screening: size of the screen depends upon the

grinding equipment used and type of equipment used for
tablet preparation

 Compression : A typical complete tablet manufacturing cycle

consists of the four steps

◦ Die filling,

◦ fill weight adjustment,

◦ Tablet compaction and

◦ Tablet ejection (from the die).

 Tablet punching machine
 A standard tablet compression machines consist of following
components.

 Hopper: for temporary storing the material for compressing.

 Cam tracks: for guiding the movement of the punches.

 Dies: for controlling the size and the shape of the tablet.

 Punches: for compressing the

materials within the dies.

• The tablet presses may be:

o Single punch

o Rotary punching machine

Tablet punching
 Rotary punching machine (16 station, 49 station)
• Rotory because the head which holds upper punches, dies and
lower punches in place rotates

• As the head rotates the punches are guided up and down by

cam tracks which control the sequence of filling, punching
and ejection
• Portions holding the
punches are called
turrets and portion
containing the die as
die table
• [Link]
watch?v=ldNoqCC6oBI
 Sequence of events
 Granulations stored in the hopper empties into feed frame
 Speading of granulations for filling of the dies
 Pull down cam track allows the dies to over fill
 Weight control cam decreased the amount to desired level. Wipe
off blade removes excess amount
 Lower punch travels over the lower compression roll simultaneously
upper punch travels beneath the upper compression roll
 Upper punch enter a fixed distance into the die while lower punches
raise to compress and compact the granulations
 Upper punches withdrawn and lower punches raises to bring the
tablet slightly above the die
 Ejector knob decided the ejection of tablet
Compression and consolidation in tablet
manufacturing
Tablet manufacturing or the tablet compaction consists of two

steps:

 Compression (volume reduction)

For volume reduction granules/powder is placed in a die and

then a set of punches reduce the volume by pressing the
powder.

 Consolidaion (shaping in tablet)

The process of compaction can be described by a set of

events or phases
 The process of compaction of a powder include following steps:
 Particle rearrangement
 Elastic, viscoelastic and plastic deformation of particles
 Fragmentation of particles
 Formation of interparticulate bonds
 The initial volume reduction of particles leads to their
rearrangement which in turn results into a closer packing
structure.

 After a threshold rearrangement point , further reduction

beyond the point in compact volume results in the elastic
(reversible), viscoelastic and plastic (irreversible)
deformation of the particles along with the particle
fragmentation.

 These processes finally lead to the formation of

interparticulate bonds which may later break thereby
facilitating further compression or compaction.
 The type of bonds during tablet formation may be of
following types:

◦ Mechanical interlocking (between irregularly

shaped particles)

◦ Interparticulate attraction force s (e.g.,

intermolecular force s, such as Van der Waal forces.
electrostatic forces. and hydrogen bonding)

◦ Solid bridges (due to melting)

Processing problems
 Capping and lamination
◦ Partial or complete separation of top or bottom crowns
◦ Separation of a tablet into one two or more distinct layers

◦ Causes
◦ Air entrapment in the granules
◦ Rapid decompression
◦ Deep concave punches
 ◦ Use of too dry granulation tends to cap or laminate for
lack of cohesion

◦ Incorrect setup at the press

 Remedy:
◦ Precompression- Slowing the rate of tableting or
reducing the final compression pressure.

◦ Use of flat punches

◦ Maintenance of optimum moisture in the processing of

granulation

◦ Use of special durable dies with tungsten carbide insert

Picking and sticking
 Picking Surface materials from a tablet that is sticking to
the punch and being removed from the tablet surface is
picking.

 Sticking It refers to tablet materials adhering to the die

wall.

 Causes:

 Adhesion of materials to the punch faces

 Over-wetting by under-drying, or by poor tablet quality.

 Tablet material sticking to the punch tips with engraving or

embossing
 Remedy:

 Use of large lettering on punches with small diameters

 Reformulation of tablets to large size

 Plating of the punch faces with chromium

 Addition of colloidal silica to the granules as polishing

agents

 Use of more or new binder to increase cohesiveness

of tablets

 Addition of more high melting point lubricants/

reduction of low m.p. lubricants
 Mottling It is an unequal distribution of colors on a tablet with
light and dark areas on tablet surface.

 Causes:

◦ Use of a drug whose color differs from tablet excipients

◦ Use of a drug whose dehydration products are colored

◦ Migration of dyes to the surface of a granulation during

drying

 Remedy:

◦ Changing the Solvent system

◦ Reduction of drying temperature

◦ Dispersing a dry color additive during powder binding steps

 Weight Variation: Variation of tablet weight beyond the
acceptable limits
 Causes
◦ Non uniform granule size and size distribution
◦ Poor Flow through the feed frame
◦ Punch variation
◦ Poor design of the granulation hopper
◦ Poor mixing
 Remedy:
◦ Addition or increase of a glidant like talcum, colloidal silica.
◦ Use of vibrators attached to the hopper
◦ Use of well-designed hopper
 Double Impression: Faulty engraving by punches with
monogram or engraving

 Causes:

Slight rotation of punch after precompression

 Remedy:

using non-rotating cam track

 Evaluation of tablets
 General appearance of a tablet:

 Identity and general elegance is essential for consumer

acceptance, for control of lot-to- lot uniformity and tablet-
to-tablet uniformity.

◦ size,

◦ shape,

◦ color,

◦ presence or absence of odor,

◦ taste
 Size & shape of tablet dosage form

◦ It can be dimensionally described & controlled.

◦ The thickness of a tablet is only variables.

◦ Tablet thickness can be measured by micrometer or

by other device.

◦ Tablet thickness should be controlled within a ± 5 %

variation of standard value

 Unique identification marking on tablet:

Embossing, engraving or printing. These markings include

company name or symbol, product code, product name etc
 Organoleptic properties:
◦ Color distribution must be uniform with no mottling.
◦ For visual color comparison compare the color of sample
against standard color.
 Thickness test
◦ Thickness is an unofficial test .
◦ Thickness of the tablet is inversely proportional to
hardness i.e. increase in hardness decrease the thickness
& vice versa.
◦ Thickness of tablet is measured by Vernier
caliper/screw gauge.
◦ It is determined for 10 tablets.
 Hardness:
 Tablet requires a certain amount of strength or hardness and
resistance to friability to withstand mechanical shocks of handling
in manufacture, packaging and shipping.
 Hardness generally measures the tablet crushing strength.
 It is the load required to crush the tablet when placed on its edge.
 Why do we measure hardness?
 To determine the need for pressure adjustments on the tableting
machine.
 Hardness can affect the disintegration.
 So if the tablet is too hard, it may not disintegrate in the required
period of time. And if the tablet is too soft, it will not withstand the
handling during subsequent processing such as coating or packaging.
 Factors affecting the hardness
◦ Compression of the tablet and compressive force.
◦ Amount of binder. (More binder à more hardness)
◦ Method of granulation in preparing the tablet (wet
method gives more hardness than direct method, Slugging
method gives the best hardness).
◦ Limits: 5 kilograms minimum and 8 kilograms
maximum.
◦ Make hardness test on 5 tablets and then take the average
hardness.
◦ Hardness testers: Erweka Pfizer Schleuniger Monsanto
Strong-cobb
 Friability
 It is the tendency of tablets to powder, chip, or
fragment and this can affect the elegance appearance,
consumer acceptance of the tablet, and also add to
tablet’s weight variation or content uniformity
problems.

 Friability is a property that is related to the hardness of

the tablet.

 An instrument called Roche friabilator is used to evaluate

the ability of the tablet to withstand abrasion in packaging,
handling, and shipping.
Weight Variation

 20 tablets weighed and each tablet is compare with the

average weight of all the tablets

 NMT 2 tablets should be outside the % limit

 No tablet differs by more than 2 times the % limit

As per USP As per IP

Avg weight % allowed Avg weight % allowed
130 mg or less ±10 ≤80 mg ±10
130 – 324 mg ±7.5 > 80 ~ 250 mg ±7.5
> 324 mg ±5 > 250 mg ±5
Potency  For low dose drugs: ±10%
 For high dose drugs: ±5%

Content uniformity
 Reasons: Non uniform distribution, Segregation and Tablet
weight variation

 30 tablets taken

 10 assayed individually

 9 out of 10 must contain NLT 85% or more than 115%, 10th

may be ±25%

 If not, then remaining tablets must be assayed, none should

be outside ± 15%
 Disintegration USP
 6 glass tubes, 3 inches long, open at the top, and held
against 10mesh screen at the bottom end of a basket
rack assembly

 One tablet placed in each tube, and positioned in a 1L

beaker (water, simulated gastric fluid, simulated intestinal
fluid) at 37±2ºC.

 The basket assembly is moved up and down through a

distance of 5-6cm at a frequency of 28-32 cycles/min

 Such that the tablets remain 2.5 cm below the surface on

liquid on upward movement and 2.5 cm above the
bottom on downward movement
 Disintegration :

◦ When all the particles must pass the 10 mesh screen

◦ Must be a soft mass with no probably firm core

 DT time changes with different type of tablets

◦ USP uncoated tablet: 5-30 min

◦ Enteric coated tablets;

 No disintegration in gastric fluid upto 1 hr

 Same tablets are to disintegrate in intestinal fluid in

2hr plus time specified in monograph
Dissolution
 “Dissolution is defined as the process by which a known
amount of drug substance goes into solution per unit
of time under standardized conditions.”

 The test is performed

◦ for characterizing the bio-pharmaceutical quality

of a product at different stages in its lifecycle.

◦ For choosing between different alternative

formulations for further development
Need of Dissolution Testing
 To help assure lot-to-lot uniformity: it is a very
discriminating and useful control over manufacturing
variables.
 To guide formulation development
 To help establish stability/expiration dates
 To demonstrate to FDA that products after scale up and
post-approval changes are bioequivalent to the originally
approved product.
 When correlated with in vivo data, dissolution may be
used instead of human biostudies.
 Used without in vivo correlation for minor changes.
 Dissolution:

 It is a two steps process

Step 1- Molecules released from dosage form to media

creating a saturated layer/stagnant layer, adjacent to
the solid surface.

Step 2- Drug diffusion as per concentration gradient

Various dissolution apparatus as per IP and USP

As per IP

Apparatus I : Basket type

Apparatus II: Paddle type

USP Dissolution test apparatus
 A cylindrical vessel with
hemispherical bottom, capacity
1000mL with inner diameter
98-106 mm

 Motor with speed regular

controls the rpm of paddle
(shaft attached to a blade
forming a paddle)

 Temperature maintained 37 ±
5ºC
 Dissolution Test (U.S.P.)

 For dissolution test Pharmacopoeias specify dissolution test

medium and volume,

◦ type of apparatus to be used,

◦ rpm of the shaft,

◦ time limit of the test and

◦ assay procedure

 Perform dissolution test and check whether acceptance

criteria is met
Acceptance criteria

Q= amt of dissolved drug as per monograph

Values of t 50%, t 90% and percentage dissolved in 30 minutes
are used as guides