Tablet

Fantahun Molla (Asst.Professor, MSc, B.Pharm)

1
 Chapter objectives

• Explain the advantage and disadvantage of tablets

• Explain the quality attributes of tablet

• Discuss types of tablet

• Talk about pharmaceutical excipients required for

tablet formulation

• Describe methods of preparations of tablet

2
 Chapter objectives

• Discuss problems in tabletting and troubleshooting

mechanisms for the problems

• Explain quality evaluation methods of tablet dosage

forms

3
 Introduction

Definition:
 Tablet is a hard compressed solid dosage form

 Contain unit dose of one or more medicaments

with or without excipients

 They can be round, oblong, or cylindrical in shapes.

4
 Advantage of tablet
From patients stand point:

– They are easy to carry and swallow

– They are attractive and elegant in appearance

– Unpleasant taste can be masked by sugar coating

– They do not require any measurement of dose

• Some of the tablets are divided into halves and quarters by

drawing lines during manufacturing to facilitate breakage

whenever a fractional dose is required.

5
 Advantage of tablet…
From the standpoint of manufacturer
• Tablets provide administration of even minute dose of
drug in an accurate amount

• Tablets provide prolonged stability to medicament

– They have the best combined properties of chemical,
physical/mechanical and microbiological stability of all
the oral dosage forms

– The incompatibilities of medicaments and their

deterioration due to environmental factors are less in
tablet forms 6
 Advantage of tablet…

From the standpoint of manufacturer…

• The manufacturing cost of tablets is low as compared
to other dosage forms: the easiest and cheapest to
package and ship

• Tablets can be formulated as a special release of

products such as enteric or delayed release products

7
 Disadvantage of tablet

• The manufacturing of tablets requires a series of unit

operations which leads to product loss at each stage in
the manufacturing process

• Some drugs may be difficult or impossible to formulate

and manufacture as a tablet

– Amorphous
– Hygroscopic
– Drugs with low density character
– Poor wetting
8
 Disadvantage of tablet

• Drugs having bitter taste, unpleasant odor or drugs

sensitive to oxidation require special treatment
like coating or encapsulation

Increase their production cost

• Swallowing of tablets especially by children and

critically ill patients is very difficult.

9
 Quality attributes of tablet

– The tablet should include the correct dose of the

drug

– The appearance of the tablet should be elegant,

and its weight, size and appearance should be
consistent

– The tablet should be packed in a safe manner

– The tablet should be formulated into a product

10
acceptable to the patient
 Quality attributes of tablet…
• The tablet should be of sufficient mechanical strength
to withstand fracture and erosion during handling at all
stages of its lifetime

• The tablet should be chemically, physically and

microbiologically stable during the lifetime of the
product

• The drug should be released from the tablet in a

controlled and reproducible way
11
 Quality attributes of tablet…

• The tablet should be biocompatible,

– i.e. not include excipients, contaminants and

microorganisms that could cause harm to patients

12
 Types of tablet
• Tablets are classified according to their route of
administration or function

• Tablets ingested orally: • Tablets used in the oral

– Compressed tablets cavities
– Buccal tablets
– Multiple compressed – Sublingual tablets
tablets – Lozenges
– Enteric coated tablets • Tablets administered by other
– Sugar coated tablets routes
– Implantation tablets
– Film coated tablets – Vaginal tablets
– Chewable tablets • Tablets used to prepare
solutions
– Effervescent tablets
– Hypodermic tablets 13
 Types of tablet…

TABLETS INGESTED ORALLY

– These tablets are designed to be swallowed except the
chewable tablets
– The tablets covered in this category are:

CONVENTIONAL COMPRESSED TABLETS

– These tablets are designed to provide rapid
disintegration and hence rapid drug release, and
represent a significant proportion of tablets that are
clinically used 14
 Types of tablet…
MULTIPLE COMPRESSED TABLETS
• Such tablets are prepared by compressing additional
tablet granulation on a previously compressed granulation.

• The operation may be repeated to produce multilayered

tablets of two or three layers.

• These tablets are prepared to separate physically or

chemically incompatible ingredients or to produce repeat
action or prolonged action products

15
 Types of tablet…
ENTERIC COATED TABLETS:
• By-pass the stomach and get disintegrated in the
intestine only

 Coated with polymers resistant to acidic pH but

disintegrated in the alkaline pH

 Cellulose acetate phthalate (CAP)

 Cellulose acetate butyrate (CAB)
 Hydroxypropylmethylcellulose succinate

 Methacrylic acid co-polymers (Eudragit)

• E.g. Enteric-coated aspirin tablet 16
 Types of tablet…

SUGAR COATED TABLETS:

• These are compressed tablets containing a sugar coating

– To mask the bitter, unpleasant odour and taste of the

medicament

– To safeguard the drug from atmospheric effects

– To make the tablet elegant

17
 Types of tablet…

FILM COATED TABLETS:

– The compressed tablets having a film coating of some polymer

substance

 Hydroxy propyl cellulose

 Hydroxy propyl methyl cellulose (HPMC)

 Ethyl cellulose (EC)

– Replace sugar coating- More durable than sugar coating and can

be formed quickly

– Example: Glyburide/metformin (5 mg/500 mg) film-coated tablets

18
 Types of tablet…
CHEWABLE TABLETS:

• To be broken and chewed in between the teeth before

ingestion
• The main applications for this dosage form are:

– For children and adults: to improve easily

swallowbality
E.g. Vitamin tablets

– To accomplish a quick and complete disintegration of

tablet
E.g. Antacid tablets 19
 Types of tablet…
• For the preparation of chewable tablets sweetening
agents should be used

– Mannitol
– Sorbitol
– Lactose
– Chocolate powder
– Dextrose
– Glycerin

• These tablets do not require any disintegrating agents to

20
be present in the formulation
 Types of tablet…
TABLETS USED IN ORAL CAVITY

Buccal tablets:
• These tablets are to be placed in the side of the cheek
(buccal pouch)

• Dissolve or erode slowly without disintegration

– The drug is absorbed into the blood circulation directly

through oral mucosa – Avoid first pass effect

• Example: Fentanyl buccal tablet

21
 Types of tablet…
Sublingual tablets:

• Placed under the tongue

– Dissolve or disintegrate quickly and are absorbed

directly without passing into GIT

• Avoids first-pass metabolism

– Example: Glyceryl trinitrate sublingual tablet

22
 Types of tablet…
Lozenges

• Dissolve slowly in the mouth and so release the drug

dissolved in the saliva

• Can be used for systemic effect or local effect in the

mouth or throat

• Commonly used to treat sore throat to control coughing in

common cold.

• They may contain local anaesthetics, antiseptics,

antibacterial agents, and anti-tussives.
23
 Types of tablet…
• Common examples of fillers

– Glucose, sorbitol and mannitol- contribute to pleasant

taste
• A common binder in lozenges is gelatin

• Disintegrants are not used in the formulation

• Lozenges are prepared by compaction at high applied

pressures

– High mechanical strength and low porosity -dissolve slowly

in the mouth
24
 Types of tablet…
TABLETS ADMINISTERED BY OTHER ROUTES

Implantation tablets:

• Placed under the skin or inserted subcutaneously by

means of minor surgical operation and are slowly
absorbed

• The implants must be sterile and should be packed

individually in sterile condition.

– E.g. Contraceptives

25
 Types of tablet…
TABLETS ADMINISTERED BY OTHER ROUTES…
Vaginal tablets:

• These tablets are meant to dissolve slowly in the

vaginal cavity

– Disintegration of these tablets must be avoided

for proper retention inside the vagina

• They are used to release steroids or antimicrobial

agents

26
 Types of tablet…
TABLETS USED TO PREPARE SOLUTIONS

Effervescent tablets

• Added to aqueous solutions where they will rapidly

disintegrate and produce either a drug suspension or an
aqueous solution.

• The disintegration of the tablet is due to a chemical

interaction that occurs between two components:

– (1) an organic acid (e.g. citric acid, tartaric acid)

– (2) sodium bicarbonate in the presence of water

27
 Types of tablet…

• The evolution of carbon dioxide from this reaction

results in tablet disintegration

• Should be packaged in moisture-impermeable

packaging (typically aluminium foil)

28
Figure: Concentration of salicylates in plasma after administration
of acetylsalicylic acid tablets (1 g) Circles, effervescent tablet;
29
squares, conventional tablet
 Types of tablet…
Hypodermic tablets

• Hypodermic tablets are soft, readily soluble tablets and

originally were used for the preparation of solutions to be
injected

• These tablets are dissolved in sterile water or water for

injection and administered by parenteral route

• These tablets are not preferred now-a-days because the

resulting solution is not always sterile
30
Excipients used in the manufacture of tablets

• Excipients are pharmacologically inert materials that are

combined with APIs to

– Aid their processing into dosage forms

– Facilitate API administration to patients

31
 Excipients…
Ideal properties of Excipients:

ally
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wit racti a rm ine
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dru n
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Excipients

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eff ost St r
ect fo ling
iv e n d
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32
 Excipients…

• The type of excipient used is dependent on the process

employed

• Typically the following excipients are used in the

manufacture of conventional tablets:

 Diluents/fillers  Glidants
 Binders  Antiadherent
 Disintegrants  Miscellaneous

 Lubricants

33
 Excipients…
Diluents/fillers

• To increase the mass of the tablets that contain a low

concentration of therapeutic agent and thereby render
the manufacturing process more reliable and
reproducible.

• E.g. Dexamethasone contains 0.75 mg steroid per

tablet- diluents are added

• The dose of some drugs is sufficiently high e.g.

aspirin- no filler is required
34
 Excipients…
Diluent

Soluble Insoluble

• Soluble diluents
• Insoluble diluents
 Lactose  Calcium sulfate dihydrate
 Sucrose  Dibasic and tribasic calcium
phosphate
 Dextrose
 Starch
 Mannitol
 Microcrystalline cellulose 35
 Excipients…
• Lactose
– The most commonly used filler for tablets

– The anhydrous crystalline form - wet and dry

granulation processes

– The amorphous form - direct compression method

Amorphous form is more soluble and have better

compaction properties than the crystalline form

Amorphous form is hygroscopic and unstable

36
 Excipients…
• Disadvantages:

– Lactose reacts with amine drug bases in presence of

alkaline lubricants e.g. magnesium stearate

• Gradually discolors (dark brown) with time due to

the formation of furaldehyde

• This reaction is called Maillard reaction

– Some people are lactose intolerant

37
 Excipients…
Mannitol
• Used as fillers in chewable tablets
– Sweet taste
– Has negative heat of solution - cooling sensation in
the mouth

• Disadvantages
– Costly

– Mannitol has poor flow characteristics and usually

require fairly high lubricant level
38
 Excipients…
CALCIUM SALTS

– Dibasic calcium phosphate dihydrate (or dicalcium

orthophosphate) (DCP) [CaHPO4, 2H2O]

– Calcium sulfate dihydrate (CaSO4 , 2H2O)

• Water-insoluble, but easily wetted by water

• Fine particulate form - suited for granulation method

• Aggregated form - suited for direct compression

– Excellent flow and compression properties

39
 Excipients…

• Disadvantage:
– Divalent cation (Ca++) form insoluble complexes and
salts with number of amphoteric or acidic
functionality antibiotics, which generally reduces
their absorption

40
 Excipients…
MICROCRYSTALLINE CELLULOSE (MCC)
– Have both crystalline and amorphous regions
– Available in several grades with different degrees of
crystallinity and physicochemical properties
– Trade Name : Avicel – is a directly compression
material
– Acts as diluent, binder and disintegrating agents
– Disadvantage
• The price is higher than more commonly used
diluents 41
 Excipients…
Binder
• Agents used to impart cohesive qualities to the powdered

material are referred to as binders or granulators.

• Binders can be added to a powder in different ways:

– As a dry powder which is mixed with the other

ingredients before wet agglomeration- Dry binder

– As a solution which is used as an agglomeration liquid

during wet agglomeration- Solution binders

42
 Excipients…

• Dry binders Solution binders

 Microcrystalline cellulose Starch

Sucrose
 Cross-linked
Gelatin
polyvinylpyrrolidone
Polyvinylpyrrolidone
 Polyethylene glycol
Hydroxypropylcellulose
 Methyl cellulose
Polyethylene glycol

43
 Excipients…

Granulating agents

• Provide proper moisture to convert fine powders in damp

mass

• Example: Water, ethanol, Acetone

44
 Excipients…

Disintegrants

• A disintegrant is a substance added to tablet to

facilitate its breakup or disintegration after

administration in the GIT.

– Ideally, the tablet should break up into individual drug

particles in order to obtain the largest possible

effective surface area during dissolution.

45
46
 Excipients…
Mechanisms by which disintegrants elicit their effect:

I. Disintegrants may increase the porosity and

wettability of the compressed tablet matrix

– GIT fluids may readily penetrate the tablet matrix

and thereby enable tablet breakdown to occur

• Example
– Starch (Dry form)
– MCC

– Sodium starch glycolate (the sodium salt of the carboxymethyl

ether of starch)
47
 Excipients…

Example:
II. Disintegrants may operate
 Sodium starch glycolate
by swelling in the presence
 Croscarmellose sodium (a
of aqueous fluids.
cross-linked sodium
– Increase in the internal
carboxymethyl- cellulose)
pressure within the
 Crospovidone (a cross-
tablet matrix
linked polyvinylpyrollidone)

 Pregelatinised starch
48
 Excipients…

III. Tablet disintegration may also be mediated by the

production of gas whenever the tablet contacts aqueous
fluids.

– This is the mechanism of disintegration of

effervescent tablets.

49
 Excipients…

Lubricants
• Prevents adhesion of the tablet material to the surface

of dies

– Lubricants act at the interface between the face of

the die and the surface of the tablet

• Reduce the friction at this interface during

ejection of the tablet from the tablet press

50
 Excipients…

• Inadequate lubrication of this interface results in

the production of tablets with a pitted surface

– Due to the inability of the tablet surface to

detach from the surface of the tablet die

51
 Excipients…
• Types of lubricants:
– Insoluble lubricants

– Soluble lubricants
Insoluble lubricants
• Added to the final mixing stage prior to tablet compression
• Factors to be considered

– The concentration of lubricant used

 High lubricant concentrations:

Reduced rates of disintegration and dissolution

Failure of the quality control tests for these parameters.
52
 Excipients…

– The time of mixing of the lubricant with the

granules/powders

Over mixing (in terms of both shearing stress

and time) may adversely affect tablet
disintegration and drug dissolution

• Examples of insoluble lubricants that are commonly

used are:
– Magnesium stearate
– Stearic acid
53
 Excipients…
Soluble lubricants
• Do not affect time required for tablet disintegration and
hence drug dissolution.

• The efficacy as a lubricant is less than that of insoluble

lubricants

• Examples of soluble lubricants include:

– Polyethylene glycol (PEG).
• PEG 4000, 6000 and 8000- used as lubricants in the
manufacture of tablets

– Lauryl sulphate salts

– Polyoxyethylene stearates 54
 Excipients…
Glidants
• Enhance the flow properties of the powders within the
hopper and into the tablet die in the tablet press
• They are able to locate themselves within the spaces
between the particles/granules.
– Reduced friction between the powders/granules and
the surfaces of the hopper
• Glidants are typically so hydrophobic
– High concentration could adversely affect tablet
disintegration and drug dissolution.
55
 Excipients…

• Examples

– Talc: Chemically talc is hydrated magnesium

silicate (typically Mg6(SiO2)4(OH)4)

– Colloidal silicon dioxide

– Starch

56
 Excipients…
Antiadherent

• Reduce adhesion between the powder and the punch

faces

• Many powders are prone to adhere to the punches-

sticking or picking

– Affected by the moisture content of the powder

• Such adherence is especially prone to happen if the

tablet punches have markings or symbols.

57
 Excipients…

• Examples of antiadherent

– Magnesium sterate

– Talc

– Starch

58
 Excipients…

• Miscellaneous excipients used in the formulation of

tablets

– Sweetening agents/flavours

– Colours

– Surface-active agents

59
 Excipients…
Sweetening agents
• Sweetening agents are employed to control the taste and
hence the acceptability of tablets.
• Example

– Sugar
• Mannitol: 72% as sweet as sugar, cooling & mouth
filling effect
• Saccharin-Artificial sweetener: 500 times sweeter
than sucrose
Disadvantage: it has a bitter after taste
60
 Excipients…

• Aspartame : widely replacing saccharin

Disadvantage – lack of stability in presence

of moisture

Colorant

• Colored tablets are generally formulated either to

improve the appearance or to identify the finished

product uniquely
61
 Excipients…
Surface-active agents
• Surface-active agents may be incorporated into tablets

– To improve the wetting properties of hydrophobic

tablets and hence increase the rate of tablet
disintegration.

– To increase the aqueous solubility of poorly soluble

drugs in the gastrointestinal tract and, as a result,
the rate of dissolution of the active agent will
increase

• Example: Sodium lauryl sulphate 62

Manufacturing of Tablets

63
 Manufacturing of tablets

• There are two main methods by which tablets are

manufactured:

– Granulation

– Direct compression

• The choice of manufacturing process employed is

dependent on several factors:

– The compression properties of the therapeutic agent

64
 Manufacturing of tablets

– The particle size of the therapeutic agent and

excipients

– The chemical stability of the therapeutic agent

during the manufacturing process

65
 Manufacturing…
Granulation
• Granulation is a unit operation in which mixed powders are

aggregated into and retained as larger particles

Particles before Granule

granulation

• “Mostly the materials, intended for compression

into tablets are converted into granules” – Why?
66
 Manufacturing…
Fine powders

• Do not flow evenly through hopper high weight

variation of the compressed tablets

• Poor compaction property

• Segregation of ingredients happen and hence affect

content uniformity

• Air imprisoned during compression capping

• Higher incidence of dust production 67

 Manufacturing…
Granules

• Flow evenly through hopper due to the spherical shape

and tablets of uniform weight are produced

• The compaction properties of granules are improved

– Due to the presence of the binder component

leading to greater intergranule adhesive interactions

• Ingredients are bound together via granulation hence

little or no segregation
68
 Manufacturing…

• Granules have more knitting power and hence up on

compression sound tablets are formed

• Lower incidence of dust production

69
 Manufacturing…
Granulation mechanisms

• To form granules

– Bonds must be formed between powder particles so

that they adhere

– The bonds must be sufficiently strong to prevent

breakdown of the granule to powder in subsequent

handling operations

70
 Manufacturing…

• The primary bonding mechanisms between particles are:

– Adhesion and cohesion forces in the immobile liquid

films between individual primary powder particles

– The formation of solid bridges after solvent

evaporation

– Attractive forces between solid particles

– Mechanical interlocking

71
Manufacturing…

72
 Manufacturing…

Methods of granulation

– Wet granulation

– Dry granulation

73
 Manufacturing…
Wet granulation
– Wet granulation involves the massing of a mix of dry primary
powder particles using a granulating fluid

– Steps
I. Milling of the drug and excipients

II. Weighing

III. Mixing

IV. Wet Massing

V. Wet Screening

VI. Drying

VII.Dry Screening
74
VIII.Lubrication of granules
 Manufacturing…
Steps in wet granulation
Step-I Milling of the drug and excipients
– Active ingredients, excipients etc are milled to obtain
a homogeneity in the final granulation
Step-II Weighing
– Weighing should be done in clean area
– In the weighing area all the ingredients must not be
brought at a time to avoid cross-contamination

75
 Manufacturing…

Step-III Mixing

• API + Diluent

• Commonly used blenders are:

– (a) Double cone blender

– (b) V – blender

– (c) Ribbon blender

76
 Manufacturing…

Step-IV Wet massing

– Wet granulation forms the granules by binding the

powders together with an adhesive

– Binder can be added as:

• Dry binder

• Binder solution

77
 Manufacturing…
Method-I (Dry binder)

Drug + Diluent Method-II (Binder solution)

Drug + Diluent
Binder Solution is added

Binder Solution is added

Method-II (Binder solution) will give more cohesiveness than

method-I if the amount of binder remains constant 78
 Manufacturing…
• N.B.

The powder must be moist and not paste

There is a limit to the amount of solvent that

may be incorporated

To determine the proper moistening,

The moist mass is pressed by two fingers

If fragments of granules are formed and not

powder then the blending is stopped 79

 Manufacturing…

• If granulation is over-wetted

– The granules will be hard

• Requiring considerable pressure to form the

tablets, and

• The resultant tablets may have a mottled

appearance

80
 Manufacturing…

• If the powder mixture is not wetted sufficiently

– The resulting granules will be too soft

• Breaking down during lubrication and causing

difficulty during compression

81
 Manufacturing…

Step-V Wet Screening

– Wet screening process involves converting the moist

mass into coarse granular aggregates

• by passing through granulator equipped with

screens having large perforations (# 6 – 8 mesh

screen)

– Purpose
82
• Increase surface area to facilitate drying
 Manufacturing…
Step-VI Drying
– Drying is usually carried out at 600C
– Depending on the thermolabile nature of the drug the
temperature can be optimized
– Drying is required in all wet granulation procedures to
remove the solvent
• But is not dried absolutely because it will pose
problems later on
• Certain amount of moisture ( 1 – 4 %) should be left

83
 Manufacturing…
Step-VII Dry Screening
– After drying, the granule size is reduced by passing
through smaller mesh screen
–  Mesh size number (# 12, # 14, #16, #20)
 The mesh number system is a measure of how many
openings there are per linear inch in a screen
 Mesh # 6 = 3.36 mm
 Mesh # 14: 1.19 mm
 Mesh #7 = 2.83 mm
 Mesh # 16: 1.00 mm
 Mesh # 8 = 2.38 mm
 Mesh # 20: 0.841 mm
 Mesh # 12: 1.41 mm 84
 Manufacturing…
Step-VIII Lubrication of granules
• After dry granulation, the lubricant is added as a fine powder

• It is usually screened onto the granulation through 60 or 100 mesh

nylon cloth to eliminate small lumps as well as increase the covering
capacity of the lubricant

• The lubricant is blended very gently using tumbling action to maintain

the uniform granule size

• Since, the very nature of lubricant produce hydrophobic surface on

the particle hence over blending prevents the inter granule bonding

that takes place during compression 85

 Manufacturing…
Example of wet granulation formulae
Ingredients Quantity/tablet Remarks

Ferrous sulfate (dried) 300 mg Active ingredient

Corn Starch 60 mg Diluent

20% sugar solution q.s. Binder

Sodium starch glycolate 45 mg Disintegrant

Talc 30 mg Glidant &

Antiadherent

86
Magnesium stearate 4 mg Lubricant
 Manufacturing…
Method of Preparation
FeSO4 + Corn Starch
 Mix
 Moistened with sugar solution
 Passed through #12
Wet granules
 Dried on tray dryer (Temp: 60 – 650C, over night)
 Dry Screened through #18
Dry granules  sodium starch glycolate +talc +Mg-stearate
 Compression
TABLET 87
 Manufacturing…
DRY GRANULATION

• Dry granulation is followed in situations where

i. The effective dose of a drug is too high for direct

compaction

ii. If the drug is sensitive to heat, moisture or both,

which precludes wet granulation

• E.g. Many aspirin and vitamin formulations

88
 Manufacturing…

• Slugging is the key step in dry granulation

– Slug may be described as poorly formed tablets or,

may be described as compacted mass of powdered

material

• Purpose

– To impart cohesiveness to the ingredients, so as to

form tablets of desired properties

89
 Manufacturing…

• Method

– It is done either by

 High capacity heavy duty tablet press

 Roller compactor

90
 Manufacturing…
I. High capacity tablet press

 Large tablets are made because

• Fine powders flow better into large cavities

• Large slugs reduces production time

– The punches are flat faced

– The slugs are formed by compression

– The compressed slugs are comminuted in desired mesh

screen 91
 Manufacturing…

II. Roller compactor

– It consists of two grooved rollers

– Powder is flowed into the grooves and compressed

mass is produced as the rollers rotates

– Distance between two rollers can be adjusted

92
 Manufacturing…

Fig: Granulation of a powder using roller compaction 93

 Manufacturing…
• Main steps in dry granulation

Using a tablet press Using a roller compactor

Powder + Lubricant Powders

 
Slugs Slugs
 
Granules Granules
 
Lubricated Lubricated
 
Compressed Compressed
• Advantages of roller compactor over tablet press
– Very high production rate
– Lubrication is not required in the primary stage 94
 Manufacturing…
• Advantages of dry granulation over wet granulation

– No application of moisture and heat

– Suitable for drugs susceptible to either moisture
or heat or both
– Involves less steps and hence less time, working space
and energy is required than that of wet granulation
• Wet granulation is more popular than dry
granulation???

– Former will meet all the physical requirement for

the compression of good tablets 95
 Manufacturing…
 Example of dry granulation
Preparation of Aspirin tablets
Ingredients Quantity required Remarks
per tablet

Aspirin (#20 325.0 mg Active ingredient

mesh)

Starch (dried) 32.5 mg Diluent /

Disintegrant

Mg-stearate 0.1 mg Lubricant

96
 Manufacturing…
• Method

Aspirin + Starch + Mg-stearate

 Mixed in twin-shell blender for 10 mins
Powder blend
 Compressed into slugs of 1 inch diameter flat-face punch
Slugs
 Size reduction by granulator
Granulation (# 16 mesh)

Compressed
97
 Manufacturing…
Direct compression
• Manufacture of tablets by direct compression

– Involves powder mixing and subsequent compression of

the powder mix, thereby avoid the need for granulation
(and related unit operations)

– Steps Milling

Weighing

Sieving

Blending

98
Compression
 Manufacturing…
Advantages of direct compression
• There are fewer processing steps (unit operations)

– More cost-effective than other methods

• Does not require the use of water and heating

– Suitable for heat and moisture sensitive product

• Lubrication is performed in the same vessel as powder

mixing

– Reduce both transfer losses and contamination of

equipment
99
 Manufacturing…
Disadvantages of direct compression
• Specialist (and more expensive) excipients are required

• The final tablets produced by direct compression tend to

be softer than those produced by wet granulation,

– More difficult to process using post-tableting

techniques, e.g. film coating.

• Direct compression is not used if a colorant is required in

the formulation

– Due to the mottled appearance of the resulting dosage

form 100
 Tablet compression machines

• Tablet compression machines is used to form a hard mass

• There are two types of press in common use during

tablet production:

– The single-punch press (Single station, eccentric

press)

– The rotary press (Multistation press)

101
 Tablet compression machines

• The single-punch
press
 A single-punch
press possesses
one die and one
pair of punches

102
 Tablet compression…
The function of each components
• Hopper: Supply the granules to be compressed to the die cavity

• Tablet wt adjuster or capacity regulator: Adjust the position

of lower punch to accommodate the required granules quantity by
the die

• Ejection regulator: Adjust the position of the lower punch so

that its highest position is at parallel with the surface of the
die.

• Die: Allows the upper and lower punches to come close together
to compress the granules

• Punches: the lower and upper punched physically compress the

granules in to tablets 103
 Tablet compression…
• The sequence of events involved in the formation of
tablets in single-punch press

• Upper punch is raised; lower

punch has dropped.

• Hopper shoe has moved

forward over die and granules
fall into die.

104
 Tablet compression…

• Hopper shoe has moved

back. Upper punch has
come down compressing
granules into tablet

• Upper punch has moved

upwards. Lower punch has
moved upwards to eject
tablet

• The cycle is now repeated

105
 Tablet compression…
Rotary press
• The dies and punches are mounted on a rotating turret
• The primary use of this machine is during large-scale
production
• Outputs of over 10,000 tablets per minute can be
achieved by rotary presses
• A rotary press operates with a number of dies and sets
of punches,
– Can vary considerably from 3 for small rotary
presses, up to 60 or more for large presses
106
 Tablet compression…

Fig: The events involved in the formation of tablets with

a rotary press
107
Tablet compression…
 Tablet compression…

Tablet tooling; punches and dies

109
 Tablet compression…

Caplet Shape Dies

Oval Shapes Dies

Round Shapes Dies

110
 Tablet compression…
Auxiliary equipments

• Mechanized feeders
– Employed to force granulations into dies

• Granulation level sensors

– Stop the press automatically when granulation level drops to a

critical level in the hopper

• Electronic weight monitoring devices

• Tablet deduster
– Remove excess powder from the tablet surface coming off the

press. 111
 Compression properties
• The dominating technique of forming tablets is by
powder compression
– Forcing particles into close proximity to each other
by confined compression
– This enables the particles to cohere into a porous,
solid specimen of defined geometry
– Because of the increased proximity of particle
surfaces accomplished during compression
• Bonds are formed between particles which provide coherence
to the powder, i.e. a compact is formed
112
 Compression properties…

• Compression vs. Compaction

– Powder compression is defined as the reduction in

volume of a powder owing to the application of a force.

– Compaction is defined as the formation of a solid

specimen of defined geometry by powder compression.

113
Compression properties…

114
Compression properties…

115
 Compression properties…

 The ideal substance for compression would have a

combination of plastic deformation and brittleness.

 Plastic deformation means that the substance will flow

under a compressive load and will remain deformed

once the load is removed.

 Brittleness indicates that a substance will fracture,

creating new surfaces that may encourage adhesion or

cohesion 116
 Stages of tablet formation
• The process of tableting can be divided into three
stages known as the compaction cycle
– Die filling
– Tablet formation/compaction
– Tablet ejection
• Die filling

– This is normally accomplished by gravitational flow of

the powder from a hopper via the die table into the
die
– The die is closed at its lower end by the lower punch117
 Stages of tablet formation…

• Tablet formation

– The upper punch descends and enters the die and the

powder is compressed until a tablet is formed.

– During the compression phase, the lower punch can

be stationary or can move upwards in the die.

– After the maximum applied force is reached, the

upper punch leaves the powder

118
• i.e. the decompression phase
 Stages of tablet formation…
• Tablet ejection
– During this phase the lower punch rises until its tip
reaches the level of the top of the die
– The tablet is subsequently removed from the die table
by a pushing device

119
Problems in tabletting and troubleshooting

• A number of technical problems can arise during tablet

manufacturing.

• Sources of tablet defects are related to:

– The properties of the powder intended to be formed

into tablets

– The design and conditions of the press and the

tooling
120
 Problems in tabletting…

• Technical properties of a powder that must be

controlled to ensure the success of a tableting

operation are:

– Homogeneity and segregation tendency

– Flowability

– Compression properties and compactability

– Friction and adhesion properties

121
 Problems in tabletting…

Common problems

Capping and lamination

• Capping

– Partial or complete separation of the top or bottom

crown of a tablet from the main body.

• Lamination

– Separation of a tablet in two or more distinct layers

122
Problems in tabletting…

123
 Problems in tabletting…
Reasons of capping and lamination

• Too dry granulation tends to cap or laminate upon

compression

– Optimum moisture level is important

• Deep concave punches lead to capping as the curved part

of such tablet expands radially while the body does not

– Flat punches eliminate this additional shear stress

124
 Problems in tabletting…

• Incorrect setup of tooling at the press machine

– E.g. If the lower punch remains below the face of

the die during ejection

• The sweep-off blade cuts of the tablet leaving

the bottom part in the die.

125
 Problems in tabletting…
Picking and sticking
• Picking

– Material from the tablet surface is stick to and being

removed by a punch.
• Significant when punch tips have engraving or
embossing

126
Picking by punch face
 Problems in tabletting…
• Sticking

– A tablet material adhering to the die wall

– Serious sticking can cause chipping of a tablet’s
edges and forms rough edges; and also retard
lower punch free movement placing unusual stress
on cam tracks and punch heads leading to damage.

Tablets with rough surfaces due to picking/sticking problems 127

 Problems in tabletting…

• Suggested solutions for these problems:

– Plating punch faces with chromium produces smooth

and non-adherent faces

– Use of colloidal silica act as a polishing agent makes

punch faces smooth and prevent material adherence

– Additional binder or change in binder type may make

granules more cohesive and less adherent

128
 Problems in tabletting…
• Low-melting-point additives like stearic acid and
polyethylene glycol soften from heating during
compression and leads to sticking;

– Their concentration should be properly optimized

• Excess moisture is responsible for sticking and further

drying can solve the problem

129
 Problems in tabletting…
Mottling
– It is an unequal distribution of color on the surface of
the tablet
– One cause of mottling may be a colored drug, whose
color differs from the color of excipients used for
granulation of a tablet.

130
 Problems in tabletting…
Tablet weight variation

– Excessive tablet weight variation can be caused by a

variety of factors

– For many granulations, the inherent poor flow

characteristics of the material may be the rate

limiting step

• Slowing down the machine may reduce weight

variation 131
 Quality evaluation
• In tablet formulation development and during

manufacturing of tablets, a number of procedures are

used to assess the quality of the tablets

Uniformity of content of active ingredient

Tablet thickness

Hardness and friability

Disintegration
132
 Quality evaluation

Uniformity of content of active ingredient

• To check the presence a constant dose of drug between

individual tablets

• Two separate tests:

– Uniformity of weight (mass)

– Uniformity of active ingredient

133
 Quality evaluation
• Uniformity of weight

– Performed by collecting a sample of tablets from a

batch and determining their individual weights

– The average weight of the tablets is then calculated

– The sample complies with the standard if the

individual weights do not deviate from the mean by

more than is permitted in terms of percentage

134
 Quality evaluation…

Tablet: USP Weight Variation Test

135
 Quality evaluation…
• Weight variation test provided good result

–When the drug substance forms the greater part of

the tablet mass

• Any weight variation indicates a variation in the

content of active ingredient

• However, in the case of potent drugs

–the excipients form the greater part of the tablet

weight

–The correlation between tablet weight and amount 136of

 Quality evaluation…

Fig: Correlation between the amount of active ingredient and

tablet weight for (a) a low-dose tablet (drug content 23% of
tablet weight) and (b) a high-dose tablet (drug content 90% of
tablet weight) 137
 Quality evaluation…

• Uniformity of content of active ingredient

– Carried out by collecting a sample of tablets followed

by a determination of the amount of drug in each

– The average drug content is calculated

– The content of the individual tablets should fall within

specified limits

• Usually between 85% to 115% of the label claim

and the standard deviation is less than 6% 138

 Quality evaluation…
• Tablet Thickness

– The thickness of a tablet is determined by:

• The diameter of the die

• The amount of fill permitted to enter the die

• The compaction characteristics of the fill material

• The force or pressure applied during compression

• Tablet thickness may be measured by hand gauge during

production or by automated equipment 139

 Quality evaluation…

Fig: Tablet thickness gauge

140
 Quality evaluation…
Tablet disintegration time
• Tablet must first disintegrate and discharge the drug to
the body fluids for dissolution.
• Disintegration time is tested by tablet disintegration tester
– It consists of six tubes of the basket
– The basket is raised and lowered (by mechanical device) in
the immersion fluid (mostly water at 37oC, unless another
fluid is specified)
• Tablets must disintegrate within the times set forth in the
individual monograph.
141
 Quality evaluation…

Diagram of a disintegration instrument for the

testing of tablet disintegration time.
142
Quality evaluation…

143
 Quality evaluation…
Hardness and friability
• Tablets should have specified amount of strength and
resistance to friability
– The balance between tablet hardness and disintegration
and dissolution should be properly optimized.
• Tablet hardness is “the force required to break a tablet in
diametric compress test”.
– A force of about 4 kg is considered the minimum
requirement for a satisfactory tablet

144
 Quality evaluation…
• Tablet hardness test
– A tablet is placed between two anvils and force is
applied between the anvils.
– Crushing strength that causes the tablet to break is
recorded

Tablet Hardness Testing machine 145

 Quality evaluation…

• Tablet friability
– Tablets that tend to powder, chip or fragment during
handling lack elegance and consumer acceptance
– Such tablets create weight variation and content
uniformity problems

• Friability test
– The test indicates the tablet’s ability to withstand
abrasion in handling, packaging, and shipment.

146
 Quality evaluation…

• Friability test…
– Done by using friability tester
– Pre-weighed tablets are paced in plastic friabilator

– It is made to revolve at 25 rpm for 100 revolutions

by dropping the tablets at a distance of 6 inches
with each revolution
– A maximum weight loss of not more than 1%
generally is considered acceptable for most
products.
147
 Quality evaluation…

Friability tester
148
 Quality evaluation…

• Dissolution

– Dissolution testing is the most important way to study,

under in vitro conditions, the release of a drug from a

solid dosage form.

– It represents an important tool to assess factors

that affect the bioavailability of a drug from a solid

preparation

149
 Quality evaluation…

Fig: Absorption of a drug from an intact tablet

150
 Quality evaluation…
• Dissolution conditions

–Temperature: 37 ± 0.5oC

–Medium: 0.1 N HCl, pH 7.4

buffer, Simulated gastric

fluid, Simulated intestinal

fluid, water

–Agitation: Mild

–Volume of the Medium:

Enough to maintain sink

condition (1000 mL) 151