TABLET DESIGN AND FORMULATION

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 Introduction…
 Extensive information is required to prepare tablets
with good quality at high standards.
Based on preformulation studies, the optimal
dosage forms are generally decided.

Fig. 2 General preformulation approaches for table

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production.
 Selection of pharmaceutical excipients

 A pharmaceutical excipient is defined as an inactive

ingredient or any component other than the active
ingredient added intentionally to the medicinal
formulation.
 Pharmaceutical excipients are also called additives,
pharmaceutical ingredients, or inactive
pharmaceutical ingredients.

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Selection of pharmaceutical excipients

 Functions of chosen excipients in tablet formulation

providing essential manufacturing technology
functions
enhancing patient acceptance
providing aid in product identification
modifying drug release
enhancing stability (antioxidant)
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 Selection of pharmaceutical excipients
 Conditions required for the use of excipients in the dosage
formulations:
 no harmful effect and listed GRAS (generally recognized
as safe)
 good stability with no drug – excipient incompatibility

 no interference in quality validation and analytical tests

 satisfaction of regulatory issues and guidelines in all

countries
 ease of accessibility, distribution, and economical cost,
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
 Types of Pharmaceutical Excipients

 Diluents or fillers
 Diluents make the required bulk of the tablet
 Many potent drugs have low dose (e.g. diazepam,
clonidine hydrochloride) in such cases diluents
provide the required bulk of the tablet
Usually the range of diluent may vary from 5-
80%.
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Diluents…

 Selection of diluent should be done after considering

properties of diluent such as:
 Compactibility,
 flowability,
 solubility,
 disintegration qualities,
 hygroscopicity, lubricity and stability
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 Types of pharmaceutical excipients…
Classification of diluents
 Tablet diluents or fillers can be divided into the
following categories:
 Organic materials - Carbohydrate and modified
carbohydrates
 Inorganic materials – Calcium phosphates and
others.
 Co-processed Diluents- Di-pac 8
Types of pharmaceutical excipients…
Classification of diluents…
1. Organic diluents
i. Sugar and Sugar alcohols
Lactose: - α-lactose monohydrate, spray dried
lactose and anhydrous lactose are widely used as
diluent.
α -Lactose monohydrate (hydrous)
 is not directly compressible
 It has poor flow properties
 α-lactose monohydrate is water soluble
 relatively inexpensive
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 Types of pharmaceutical excipients…
Classification of diluents…
 Lactose spray dried
 is directly compressible
 exhibits free flowing characteristics
 needs high compression pressures in order to
produce hard tablets.
 has high dilution potential
 Expensive
 Lactose anhydrous
 Lactose anhydrous is a directly compressible
diluent
 does not exhibit free flowing property 10
 Types of pharmaceutical excipients…
Classification of diluents…
 Sucrose
 requires high machine pressures
 possesses good binding properties
 slightly hygroscopic
 inexpensive
 Mannitol
 Mannitol is a sugar alcohol
 exhibits poor flow properties
 requires high lubricant content
 non hygroscopic
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 Types of pharmaceutical excipients…
Classification of diluents…
widely used in chewable tablets b/c of:
 its negative heat of solution
 its slow solubility
 its mild cooling sensation in mouth.
 Sorbitol
 Sorbitol is often combined with mannitol in order
to reduce diluent cost
 highly compressible diluent
 is hygroscopic in nature
 has good mouth feel and sweet cooling taste
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Types of pharmaceutical excipients…
Classification of diluents…
ii. Celluloses
Powdered cellulose
 consist of finely divided amorphous and crystalline α-
cellulose particles.
 used alone or together with other fillers such as
lactose, calcium phosphates, dextrans and others.
 possesses poor compressibility & poor flow properties
 has poor binding properties and low dilution potential
 possesses some degree of inherent lubricity
 is inexpensive
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Types of pharmaceutical excipients…
Classification of diluents…
Microcrystalline cellulose
highly compressible (perhaps the most widely used
direct-compression tablet diluent)
Hard tablets, at low compression pressures, are
usually obtained when MCC is used
exhibits fair flowability
 exhibits binding properties
possesses disintegrant activity 14
Types of pharmaceutical excipients…
Classification of diluents…

II. Inorganic diluents

 Calcium phosphates

 dihydrate and anhydrous form of dibasic calcium

phosphate and tribasic calcium phosphate.

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 Types of pharmaceutical excipients…
Classification of diluents…

 used as wet granulation and direct compression

diluents

 directly compressible

 Hard tablets are produced when calcium

phosphates are used

 exhibit good flow properties, non hygroscopic,

inexpensive and wear of tablet tooling 16

 Types of pharmaceutical excipients…,
Classification of diluents…

III. Co-processed diluents

 combining two or more materials by an appropriate
process
 are physically modified in such a special way that
they do not loose their chemical structure and
stability.
 introduced to provide better tableting properties
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Table. Co-processed diluents

Brand name Adjuvant

Cellactose MCC, Lactose

Starlac lactose, maize starch
Avicell CE MCC, Guar gum
Celocal MCC, Calcium phosphate
Di-pac sucrose, dextrin
Ludipress Lactose, PVP, cross povidone

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Types of pharmaceutical excipients…

 Binders:
 Binders are added to tablet formulations to add
cohesiveness to powders
Provides the necessary bonding to form
granules, which under compaction form a
cohesive mass or a compact which is referred to
as a tablet.

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Types of pharmaceutical excipients…

Classification of binders

Sugars Natural binders synthetic/semisynthetic

polymer
Sucrose Acacia Methyl Cellulose
Liquid glucose Tragacanth Ethyl Cellulose
Gelatin Hydroxy Propyl Methyl Cellulose
(HPMC)
Starch Paste Hydroxy Propyl Cellulose
Pregelatinized Starch Sodium Carboxy Methyl Cellulose
Alginic Acid Polyvinyl Pyrrolidone (PVP)
Cellulose Polyethylene Glycol (PEG)
Polyvinyl Alcohols
Polymethacrylates

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 Types of pharmaceutical excipients…
Characteristics of commonly used binder
Binder Specified Comments
conc.
Starch Paste 5-25%w/w - Freshly prepared starch paste is used as a binder.

5-10%w/w - processed chemically and/or mechanically to

Pregelatinize (Direct rupture part of the granules in the presence of
d Starch compression) water and subsequently dried.
(PGS) 5-7.5%w/w - contains 5% free amylose, 15% free amylopectin
(Wet granulation) and 80% unmodified starch.
- Obtained from maize, potato or rice starch.
- is multifunctional excipient (a tablet binder,
diluent, disintegrant and flow aid).
-used both in Direct Compression and Wet
Granulation.

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Types of pharmaceutical excipients…
Characteristics of commonly used binder…

Hydroxy propyl 2-5%w/w - Comparable to Methyl Cellulose.

methyl Cellulose - Used in either wet or dry granulation processes.
Polyvinyl 0.5-5%w/w - Soluble in both water and alcohol.
Pyrrolidone (PVP) - Used in wet granulation process.
- Valuable binder for chewable tablets.
- The drug release is not altered on storage.

Polyethylene Glycol 10-15%w/w - Used as a meltable binder

PEG) 6000 -Anhydrous granulating agent where water or
alcohol cannot be used.
- may prolong disintegration time when conce. is
5% or higher
- It improves the plasticity of other binders.
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 Types of pharmaceutical excipients…
Disintegrants

 Bioavailability of a drug depends in absorption of

the drug, which is affected by solubility and
permeability of the drugs
the rate of drug dissolution is greatly influenced
by disintegration of the tablet.

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 Types of pharmaceutical excipients…

 The drug will dissolve at a slower rate from a non

disintegrating tablet (limited surface area to the
fluid).
 added to tablet to induce breakup of tablet when
it comes in contact with aqueous fluid.

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Types of pharmaceutical excipients…

Mechanism of tablet disintegrants

 The tablet breaks to primary particles by one or
more of the mechanisms listed below:-
i. By capillary action
 the aqueous medium penetrates into the tablet and
replaces the air adsorbed on the particles
weakens the intermolecular bond and breaks
the tablet into fine particles
 For these types of disintegrants maintenance of
porous structure and low interfacial tension
towards aqueous fluid is necessary
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 Mechanism of tablet disintegrants…

II By swelling
 the most widely accepted general mechanism of
action for tablet disintegration
 Tablets with high porosity show poor
disintegration due to lack of adequate swelling
force.
sufficient swelling force is exerted in the tablet
with low porosity
 But, if the packing fraction is very high, fluid is
unable to penetrate in the tablet

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Mechanism of tablet disintegrants …

Disintegration of tablet by wicking and swelling 27

 Mechanism of tablet disintegrants…
III. Due to disintegrating particle/particle repulsive
forces
 Another mechanism of disintegration attempts to
explain the swelling of tablet made with ‘non-
swellable’ disintegrants.
 Guyot-Hermann has proposed a particle repulsion
theory based on the observation that non swelling
particle also cause disintegration of tablets.

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 The electric repulsive forces between particles are
the mechanism of disintegration

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Mechanism of tablet disintegrants…
IV Due to deformation.
 Hess had proved that during tablet compression,
disintegrated particles get deformed
These deformed particles get into their normal
structure when they come in contact with aqueous
media
 Occasionally, the swelling capacity of starch was
improved when granules were extensively deformed
during compression.
 This increase in size of the deformed particles
produces a break up of the tablet.
 May be a mechanism of starch and has only recently
begun to be studied. 30
 Mechanism of tablet disintegrants…

Fig. Disintegration by deformation and repulsion 31

 Mechanism of tablet disintegrants…
v. Due to release of gases
 Carbon dioxide released within tablets on wetting
due to interaction between bicarbonate and
carbonate with citric acid or tartaric acid.
 The tablet disintegrates due to generation of
pressure within the tablet.
Used to formulate very rapidly dissolving or
disintegrating tablets
 The effervescent blend is either added immediately
prior to compression or can be added into two
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separate fraction of formulation.
Mechanism of tablet disintegrants…
VI. By enzymatic reaction
 Enzymes presents in the body act as disintegrants.
 These enzymes destroy the binding action of
binder and helps in disintegration

Table. Disintegrating enzymes

Enzymes Binder
Amylase Starch
Protease Gelatin
Cellulase Cellulose and it’s derivatives
Invertase Sucrose 33
 Methods of addition of disintegrants
 Disintegrating agent can be added either:
 prior to granulation (intragranular) or
 prior to compression (i.e. extra granular) or
 at the both processing steps.
 Extra granular fraction of disintegrant (usually, 50%
of total disintegrant requires) facilitates breakup of
tablets to granules
 the intragranular addition of disintegrants produces
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further erosion of the granules to fine particles.
Types of disintegrants

1.Starch
 Before 1906 potato starch and corn starch were
used
 been replaced by certain modified starches with
specialized property
 The conditions best suited for rapid tablet
disintegration are
 sufficient number of starch agglomerates,
 low compressive pressure
 the presence of water. 35
 The concentration of starch used is also very
crucial part.
 Less conc. - insufficient channels for capillary
action
 above optimum conc. - difficult to compress

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 Types of disintegrants…
2.Pregelatinized starch
 Pregelatinized starch is produced by the
hydrolyzing and rupturing of the starch grain
 It is a directly compressible disintegrants
 its optimum concentration is 5-10%.
 The main mechanism of action of Pregelatinized
starch is through swelling.
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 Types of disintegrants…
3. Modified starch

 is modified by carboxy methylation followed by cross

linking

 eg. Sodium starch glycolate

 Primojel®.

carboxymethyl starches are also marketed as

Explotab 
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 Types of disintegrants…

 Their Mechanism are rapid and extensive swelling

with minimum gelling.
 optimum concentration is 4-6 %.
 beyond its limit, it produces viscous and gelatinous
mass
 highly efficient at low conc. (greater swelling
capacity).

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 Types of disintegrants…
4. Cellulose and its derivatives
 Sodium CMC and Carmellose sodium has highly
hydrophilic structure and is soluble in water.
 But when it is modified by internally cross linking we
get modified cross linked cellulose
 Cross carmellose Na which is nearly water insoluble
due to cross linking.
 rapidly swells to 4-8 times its original volume when
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 Types of disintegrants…
 MCC exhibit very good disintegrating properties
 is insoluble and act by wicking action
 serves as an excellent binder
 has a tendency to develop static charges in the
presence of excessive moisture content.
 Therefore, sometimes it causes separation in
granulation.
 can be partially overcome by drying the cellulose to
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 Types of disintegrants…
5. Alginates
 hydrophilic colloidal substances which has high
sorption capacity
alginic acid and salts of alginic acid.
Alginic acid is insoluble in water, slightly acidic in
reaction.
So, should be used in only acidic or neutral
granulation. 42
 Types of disintegrants…

 Unlike starch and MCC, alginates do not retard flow

and can be successfully used with ascorbic acid,
multivitamin formulations and acid salts of organic
bases.

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Types of disintegrants…

6. Ion-exchange resin
 Ion exchange resin (Ambrelite®IPR-88) has highest
water uptake capacity than other disintegrating
agents like starch and Sodium CMC.
 It has tendency to adsorb certain drugs
7. Miscellaneous
 Gas producing disintegrating agents : used in soluble

tablet, dispersible tablet and effervescent tablet. 44

 Factors affecting disintegration

Effect of fillers
 The solubility and compression characteristics of fillers

 soluble fillers vs Insoluble diluents

Effect of binder
binder capacity and conc. Disintegration
time

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Factors affecting disintegration

Effect of lubricants
 Mostly lubricants are hydrophobic
 usually used in smaller size
 inhibits the wetting and consequently tablet
disintegration.
sodium starch glycolate whose effect remains
unaffected in the presence of hydrophobic
lubricant
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Surfactants
 Surfactants decrease the hydrophobicity of the
drugs
the more hydrophobic the tablet the greater
the disintegration time.

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 Lubricants

 Agents that act by reducing friction by interposing

an intermediate layer between the tablet
constituents and the die wall
 Solid lubricants, act by boundary mechanism, results
from the adherence of the polar portions of
molecules with long carbon chains to the metal
surfaces to the die wall.
 fluid lubrication acts hydrodynamic mechanism i.e.
where two moving surfaces are separated by a finite
and continuous layer of fluid lubricant.
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 Lubricants…
 solid lubricants are more effective and more
frequently used.
 Since adherence of solid lubricants to the die
wall is more than that of fluid lubricants

 hydrophobic lubricants may cause an increase in the

disintegration time in the drug dissolution rate.

 Additional lubricant is often added to the tablet

formulations that are to be compressed with curved

face punches.
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 Lubricants…
 The amount of lubricant increases as the particle size of
the granulation decreases but its concentration should not
exceed to 1%
 Lack of adequate lubrication results in:

 tablet machine strain

 damage of lower punch heads

 Damage Lower cam track, die seats

 yield tablets with scratched edges and are often

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 Lubricants…
Classification of lubricants
 Lubricant are classified according to their water
solubility
1. Water Insoluble Lubricants
 are most effective and used at reduced conc.
these lubricants function by coating ,
their effectiveness is related with their surface
area, extent of particle size reduction, time,
procedure of addition and length of mixing. 51
 Lubricants…
2. Water Soluble Lubricants
 used when a tablet is completely soluble or

 when unique disintegration and dissolution are required

 Tablet containing soluble lubricant shows higher

dissolution rate than tablet with insoluble lubricants.
 Physical mixture of the two can lead to the best
compromise in terms of:
lubricity,
tablet strength
and disintegration. 52
Table. List of soluble lubricants

WATER SOLUBLE LUBRICANTS (%W/W)

Boric acid 1

Sodium benzoate 5

Sodium oleate 5

Sodium acetate 5

Sodium Lauryl sulfate (SLS) 1–5

Magnesium lauryl sulfate (MLS) 1-2

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Anti adherents

 Anti adherents are used to prevent sticking to

punches and die walls.
 Talc, magnesium stearate and corn starch have
excellent anti adherent properties.
 silicon oil can be used as anti adherent.

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 Fig. LIST OF ANTIADHERENTS

ANTIADHERENT RANGE(%W/W) COMMENT

Lubricant with excellent antiadherents

Talc 1–5
properties

Lubricant with excellent antiadherents

Cornstarch 3 – 10
properties

Does not give satisfactory results due to small

Colloidal silica 0.1 – 0.5
surface area. Cab-O-Sil® and Syloid®

Water soluble lubricant; excellent

DL-Leucine 3 – 10
antiadherents properties

Sodium lauryl sulfate <1 Antiadherents with water soluble lubricant

Stearates <1 Antiadherents with water insoluble lubricant

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Glidants

 Added to improve the flow properties of the material

which is to be fed into the die cavity
 Starch is a popular glidant since its additional value
of disintegrant
Concentration of starch is common up to 10%.

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 Glidants…
 Talc is a glidant which is superior to starch;

 its conc. should be limited because of its retardant

effect on disintegration profile.
Silaceous material like colloidal silica, pyrogenic
silica (0.25%), hydrated sodium silioaluminate
(0.75%) are also successfully used
 Glidants act by lowering the overall interparticulate
friction
 should be in fine state of division and appropriately
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Miscellaneous Excipients

Wetting Agents
Wetting Agents in tablet formulation aid water
uptake and thereby enhancing disintegration
 Wetting agents are mainly added when
hydrophobic drug is to be formulated into tablet.
E.g. SLS, Sodium di-isobutyl sulfo succinate

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 Miscellaneous excipients…

Dissolution Retardants
 Incorporated only when controlled release of drug is
required.

Eg. Waxy materials like stearic acid and their esters

Dissolution Enhancers
 Alter the molecular forces between ingredients to
enhance the dissolution of solute in the solvent.

Eg. Fructose, Surfactants 59

 Miscellaneous excipients…
Adsorbents
 agents that can retain large quantities of liquids.

liquids like Vitamin E can be incorporated

 Most commonly used adsorbents are anhydrous

calcium phosphate, starch, magnesium carbonate,
bentonite, kaolin , magnesium silicate, magnesium
oxide and silicon dioxide
 Silicon dioxide can play as both glidant and an
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 Miscellaneous excipients…
Buffers
 Added to maintain a required pH since a change in

pH may cause significant alteration in stability.

e.g. sodium bicarbonate, calcium carbonate, and
sodium citrate.
Antioxidants
 added to protect drug from undergoing oxidation.
E.g. ascorbic acid and their esters , alpha-
tocopherol , ethylene diamine tetra acetic acid ,
sodium metabisulfite , sodium bisulfite , citric acid ,
and tartaric acid .
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 Miscellaneous excipients…

Chelating Agents
 form complexes with trace amount of heavy metal

ions

E.g.. Ethylenediamine tetracetic acid and its salts,

 Dihydroxy Ethyl Glycine,

 Citric Acid and

 Tartaric Acid
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 Miscellaneous excipients…

Preservatives
 may be a part of tablet formulation in order to

prevent the growth of microorganisms in tablet

formulation.

Eg. Parabens like methyl, propyl, benzyl, butyl p-

hydroxy benzoate

63
Miscellaneous excipients…

 Most widely used colourants are dyes and lakes which

are FD & C and D & C approved.
 Dyes are generally applied as solution especially in the
granulating agent.
 Lakes are usually employed as dry powders for
colouring.
 In general, direct compression tablets are coloured
with lakes because no granulation step is used.
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Miscellaneous excipients…

 While employing wet granulation , care should be

taken to prevent colour migration during drying .
 In any coloured tablet, the formulation should be
checked for resistance to colour changes on
exposure to light.

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 Table of some commonly used pharmaceutical colorants
(synthetic)

FD & C COLOUR COMMON NAME

Red 3 Erythrosine

Red 40 Allura red AC

Yellow 5 Tartrazine

Yellow 6 Sunset Yellow

Blue 1 Brilliant Blue

Blue 2 Indigotine

Green 3 Fast Green

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 Miscellaneous excipients…
Flavours
 commonly used in chewable tablets as well as mouth

dissolved tablets.
 Flavors are incorporated either as solids (spray dried flavors)

or oils or aqueous (water soluble) flavors.

 Oil is usually added at the lubrication step

 b/c of its sensitivity to moisture and their tendency to

volatilize
 The maximum amount of oil that can be added to
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granulation is 0.5 to 0.75 %w/w.
 Miscellaneous excipients…
Sweeteners
 Sweeteners are added primarily to chewable
tablets.
 Saccharin is 500 times sweeter than sucrose.

Disadv. has a bitter after taste and is

carcinogenic.
 Aspartame is about 180 times sweeter than
sucrose.
lack of stability in the presence of moisture.
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Table. some of the sweeteners used in tablet formulation

Natural sweeteners Artificial sweeteners

Mannitol
Saccharin
Lactose
Cyclamate
Sucrose
Aspartame
Dextrose

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Thank you!!!

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