Industrial Pharmacy (Phar3131)

Chapter II

Tablets
By: Tsegaye N. (B. Pharm., MSc)
Content
 Introduction
 Tablet formulation
 Tablet manufacturing by direct compression
 Tablet manufacturing by granulation
 Reasons for granulation, mechanisms and methods of granulation,
 Tablet compression machines
 Stages of tablet formation
 Problems in tableting and troubleshooting
 Quality evaluation

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Introduction

 Tablet is defined as a compressed unit solid dosage form containing

medicaments with or without excipients. Or
 Solid DFs containing single dose of one or more active ingredients obtained
by compressing uniform volumes of particles
 Usually prepared with the aid of suitable excipients
 Vary in size, shape, weight, hardness, thickness, disintegration, and dissolution
characteristics and other aspects depending on intended use and method of
manufacture
 Most tablets are used in oral administration of drugs
 Others: sublingual, buccal, or vaginal

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Intro…

 Mainly for systemic drug delivery but also for local drug action
 Oral tablets may be swallowed whole, after being chewed, after being dissolved
or dispersed in water or are retained in the mouth, where the active ingredient is
'liberated’

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 Advantages  Disadvantages
 Tablets are popular dosage forms:  Multistep production
 Compact dosage forms  Not suitable for drugs with poor
 Convenient and safe way of drug solubility and absorption
administration  Some drugs may cause local irritant
 Chemical, physical and microbiological effects
stability  Not suitable for drugs with poor
 Preparation procedure enables accurate compressibility
dosing of the drug  Administration of tablets may be
 Easier to package/store and transport problematic in children and elderly
 Easier to mask the taste of bitter drugs patients
 Generally inexpensive dosage form

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Quality Attributes of Tablets

 Like all other dosage forms, tablets should fulfill a number of specifications that
should be considered during design
1. Should include the correct dose of the drug (uniform content)
2. Should be elegant and its weight, size and appearance should be consistent (patient
acceptability)
3. Drug should be released from the tablet in a controlled and reproducible way (optimal
dissolution)
4. Should be biocompatible.
5. Should be of sufficient mechanical strength
6. Should be chemically, physically & microbiologically Stable.
7. Easily manufacturable, safely packed.

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Classification of tablets

 Compressed tablets  Buccal tablets

Orally ingested tablets

 Sugar coated tablets  Sublingual tablets Tablet of oral cavity

 Film coated tablets  Dental cone

 Enteric coated tablets  Effervescent tablets
 Chewable tablets Tablet to prepare solution
 Hypoderm tablets
 Dispersible tablets
 Implant tablets
 Sustained release tablets Tablet given via other route
 Vaginal tablets

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Tablet Excipients
 Diluents (Fillers)
 Diluents are fillers used to make required bulk of the tablet when the drug dosage
itself is inadequate to produce the bulk.
 Secondary reason is to provide better tablet properties such as improve cohesion ,
to permit use of direct compression manufacturing or to promote flow .
 A diluents should have following properties:
 They must be non toxic
 They must be commercially available in acceptable grade and low cost
 They must be physiologically inert
 They must be physically & chemically stable by themselves & with the drugs.
 They must be free from all microbial contamination
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Diluents…
 They do not alter the bioavailability of drug.
 They must be color compatible.
 No single filler fulfills all these
 Different substances, mainly carbohydrates and inorganic salts are used as fillers
 Lactose is the suitable and widely used diluent for tablets
 Other diluents:
 Glucose, Sucrose
 Mannitol, Sorbitol
 Dicalcium phosphate dihydrate, Calcium carbonate
 Cellulose derivatives (e.g., MCC (Avicel®)), Starch (different sources)

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Binders/Adhesives/Granulating Agents

 Substances (used in 2–10% by weight conc. in dried/ solution binders) that promote
cohesiveness within particles
 Flow property/fluidity: produce tablets of a consistent weight and uniform strength.
 Compressibility: to form a stable, intact compact mass when pressure is applied.

 Starch Paste: Freshly prepared starch paste is used as a binder. Corn starch is
dispersed in cold purified water to make a 5 to 10% w/w suspension and then
warming in water both with continuous stirring until a translucent paste is formed.
 Hydroxypropyl Methyl Cellulose (HPMC): Used as a binder in either wet or dry
granulation processes.

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Binders….
 Polyvinyl Pyrrolidone (PVP)
 Soluble in both water and alcohol
 Valuable binder for chewable tablets
 Used as a binder in either wet or dry granulation processes
 It can be added as a solution (adhesive) in the granulating fluid or as powders
(binder)
 Promote adhesion of particles to enable a granulation to form and to maintain
mechanical strength of tablet

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Binders….

 Adhesives: gelatin and acacia solution, starch paste, liquid glucose,

 Aqueous solutions of HPMC, Na CMC, and MC or alcoholic
 Organic solvent solutions of HPMC, EC, and PVP for water sensitive drugs
 Binders: provide bonding and cohesion to the components in slugging or
tableting. Include MCC, powdered or spray dried acacia, PVP
 Best (effective) cohesion achieved with solution binders
 Both types included in formulation at relatively low concentration (2-10 %w/w)
 Most binders have retardant effect on drug dissolution

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Binders…

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 Disintegrants:
 Added to a tablet formulation to facilitate its breaking or disintegration when it
contact in water in the GIT.
 Overcome cohesive forces that keep particles together in a tablet.
 Work by drawing water into tablet, swelling, and causing tablet to burst apart.
 The best and fastest acting disintegrants hydrate and swell in the acid
environment of stomach (pH 1 to 3)
 Mechanism is the reverse of binders increase the surface area so that the
dissolution rate will increase
 Starch (traditional disintegrant -up to 10%)

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Disintegrants…

 Most effective disintegrants act by swelling (swell dramatically during water uptake)
modified starches & cellulose -1-5% w/w
 Croscarmellose (2%), cross povidone (2-5%) and sodium starch glycolate (5%) are
super disintegrants because they have high swelling capacity
 Croscaramellose swells 4- 8 times in less than 10 sec.
 Sodium starch glycolate swells 7-12 times in less than 30 sec.
 These cross-linked products swell up to 10 fold within 30 seconds when in contact with
water.
 A portion of disintegrant is added before granulation and a portion before compression,
which serve as glidants or lubricant.

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Glidants
Improve flowability of powder or granulations
 Adequate flow is essential in tabletting
 Addition of such flow promoters is critical specially during high production speeds
 Traditionally, talc (1-2%) used by weight concentration
 Today, most commonly used glidants is colloidal silica (Aerosil®) at about 0.2 %w/w
 Silica particles are small in particle size--adhere to surfaces of other ingredients - reduce
interparticle friction -- ↑flow
 Magnesium stearate, normally used as lubricant, can also promote powder flow (< 1
%w/w)
 Corn starch also improves flow.

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Lubricants
 Reduce frictions between surfaces (tablet cylindrical surface and the die-wall)
 Reduce the ejection force needed to expel the compressed tablets from the dies
 Magnesium stearate –the most widely used lubricant (≤ 1%)
 Calcium stearate, stearic acid, talc, sodium stearyl fumarate, and Mineral oil
(paraffin)
 Reduce adhesion or sticking of powdered materials to the punch faces, which would
produce a rough or pitted tablet
 Reduce sticking or picking which is affected by the moisture content of the
powder
 Other agents such as talc and starch but with limited ability

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Lubricants…

 Lubricants may have undesirable effect:

 May reduce tablet strength
 Tablet disintegration & dissolution are often retarded
 All these effects are related to the amount of lubricant used, the duration and intensity of mixing
 To avoid negative effects of the above lubricants, hydrophilic lubricants can be used
 E.g., Surfactants, PEGs, or combined with hydrophobic

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Others Additives

Flavor:
 To give the tablet a more pleasant taste or to mask an unpleasant one
Colorant:
 Added to tablets to aid identification and patient compliance
 Can be added as an insoluble powder or dissolved in the granulation liquid
or Accomplished during coating
Adsorbents, Surfactants

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Tablet Manufacturing Methods
 Tablets are made by compressing a particulate solid between two punches in a die of
a tablet press
 Formulation must have three essential attributes to be transformed into quality
tablets:
1. Must flow into the die of the tablet press sufficiently rapidly and in a reproducible
manner - to avoid content and weight variation
2. Particles of the formulation must cohere when subjected to a compressing force and
remain coherent after removal of force
3. After the compression event is complete, it must be possible for the tablet to be removed
from the press without damage to either the tablet or the press

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 Layout of Tablet Manufacturing

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Manufacturing Methods…

 Three tablet manufacturing methods

I. Wet granulation
II. Dry granulation
III. Direct compression
 Each has its pros and cons and some methods are not useful for certain drugs
 Wet granulation and direct compression are the most important, with dry
granulation used in some circumstances

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1. Wet Granulation

 A widely employed method for the production of compressed tablets

 It provide several purposes in the tablet manufacturing process:
 Improves flow by forming spherical particles with large particle size
 Improves compression characteristics -↑cohesive strength
 Homogeneous mixture is achieved- segregation is prevented
 It reduces dust

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Wet Granulation…
Process
 Wet granulation involves the massing of a mix of dry primary powder particles
using a granulating fluid.
 The fluid contain a solvent which must be volatile so that it can be removed by
drying.
 Typically liquid include water, ethanol or isopropanol either alone or in
combination.
 Water is often considered the best granulating fluid (why?)
 Wet granules formed by forcing the wet mass through a sieve

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 Wet Granulation…

 Solvent usually contains a dissolved binder, which holds the granule together
after drying
 Water takes longer to dry than organic solvents
 After drying, the granules are screened to produce appropriately sized particles
 High-speed mixer–granulators, fluidized bed granulation and drying, and an ever-
increasing use of automation make wet granulation a much more efficient and
economic.
 Nevertheless, the wet granulation process still retains many inherent disadvantages

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Disadvantages

 Involves liquid (usually water) use degradation of hydrolysable drugs

 Some drugs are also heat sensitive.
 Multi-step process: requires lots of equipment, longer time, large space, huge
money, many personnel,
 Has inevitable materials loss
 Possible migration during drying  granules with uneven drug distribution

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Unit operation of Wet Granulation

1.Weighing and Blending

 Active ingredient, diluent, and disintegrant are
mixed by mechanical powder blender 
homogeneous tablets
 Optimum mixing time beyond which the mixture may show a tendency to separate
back  segregation likely to occur when components differ markedly in
 Size,
 Density and
 Shape

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Unit operation…

2. Granulation (wet massing and screening)

 Size enlargement in wet granulation is achieved by either one or both of two
different mechanisms:
a) Particles may be stick together using an adhesive
b) Dissolution of solid particles and subsequent evaporation of liquid will form crystal
bridges
 If drug is unstable in the presence of water, then granulation can be done using non-
aqueous liquids (povidone in isopropanol) but have environmental and cost problems

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Unit operation…
2. Granulation…
 Amount of granulating fluid should be controlled  neither too wet nor too dry
Granulators
 Traditional piece of granulating apparatus is the shear granulator
 Expensive procedure of wet granulation process has been improved by the
introduction of high-speed mixer granulators
 They have agitator and chopping blades which enable mixing, wet massing and
granulation to occur in one device

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Unit operation…

2. Granulation…
 Fluid-bed granulation: all-in-one processor
 Air is passed into the powder bed from below  causes the powder particles to form a
suspension in the air and gives effective mixing  granulating fluid is then sprayed
over the particles  they adhere on collision and then dried in the heated air stream

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Unit operation…

3. Drying
 After granulation, liquid must be removed since water may lead to impairment of flow, and
chemical instability
 More traditional means of drying is the tray drier
 Hot air flows over a series of shelves on which the wet material is spread
 Compared to the FBD  Drying process is slower in tray drier.
 FBD is most commonly used device
 Each granule becomes separated from each other by jet of hot air
 Air provides an effective means of heat transfer, as well as of removing water vapor
 Wet granules are present as individual units  fluidized bed drying is a rapid process

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Unit operation…

4. Dry screening
 After drying, the granules are passed through screen of smaller opening than that used
to prepare the original granulation
 Sizing is necessary so that the die cavities for tablet compression may be completely
and rapidly filled by the free-flowing granulation
5. Second Mixing Stage (Lubrication & flow enhancing)
 Glidant, lubricant and disintegrant are added to the screened granules
 Glidant and Lubricants improve flow, reduce adhesion to die wall and punch face,
provide sheen to tablet respectively.

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Unit operation…
6. Compression

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Dry Granulation

 Alternative method that eliminates risks of drug degradation by hydrolysis and heat
involvement of wet granulation
 Components of the formulation are compressed in dry state
 Avoids heat-moisture combinations decrease degradation
 Binder is added if sufficient strength cannot be achieved by compression alone
 To apply this method, either the active ingredient or the diluent must have cohesive
properties
 Involves two compression processes

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Dry Granulation…
 There are two methods of dry granulation.
1. Slugging
2. Roller compaction
Slugging:
 After weighing and mixing the ingredients, the powder mixture is slugged, or
compressed into large flat tablets or pellets about 1 inch in diameter.
 Tablets produced at this stage (slugs) will not be of acceptable quality.
 Tablet is then milled to produce granules of the required size
 After sieving, Lubricant, anti-adherent, and glidant are added in the usual manner, and
satisfactory tablets are formed by compression.
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Unit operation…

Roller Compaction:
 Powder mixture passed between two contra-rotating cylindrical rollers to form
sheet/film of compressed material
 Broken down to a product of granular size and then recompressed
 Both methods require addition of lubricant prior to the first compression
stage, though more lubricant will probably be needed before the second
compression

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Unit operation…

Advantages:  Disadvantages:
 Useful for moisture sensitive drugs  Lots of force used to compress the dry
 Fewer steps and equipment than wet mixture
granulation  Makes very hard granules
 Less loss of materials granulators disintegration/dissolution can be
 e.g., transfer steps (mixer) affect
 May be less expensive  The drug/excipient mix must be
 Less time-consuming compressible on its own

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