tablets_part_1.pdf

O6U, FACULTY OF PHARMACY, PHARMACEUTICS 3, DR.OSAMA ELNAHAS
By:
DR. Osama Elnahas
PHD of pharmaceutics and industrial pharmacy
o6u, Faculty of Pharmacy
Egypt

objectives
• After reading this chapter, the student will be able to:
• 1. Differentiate between the various types of tablet dosage forms.
• 2. Compare and contrast advantages and disadvantages of the various types of
tablet dosage forms.
• 3. List categories of inert ingredients, with examples, which are employed in
the manufacture of compressed tablets.
• 4. State quality standards and USP compendial requirements for tablets.
• 5. Differentiate between the various types of modified-release dosage forms.
• 6. Compare and contrast advantages and disadvantages of the various types of
modified-release dosage forms.
• 7. List physical-chemical characteristics of drugs that make them candidates
for an extended-release dosage form.
• 8. Explain microencapsulation, embedding, ion exchange, and osmotic pump
as these apply to modified-release dosage forms.

O6U, Faculty of pharmacy, Pharmaceutics 3, Dr. Osama Elnahas

Systemic effect Local effect
Tablet should be (Quality attributes):
Accurate dose Elegant (weight, size, appearance)
Biocompatible
Drug release in a controlled & reproducible way
Hard to resist fracture and erosion during handling
Chemically, physically, microbiologically stable)

Critical Quality Attributes
•CQA determination helps the formulator to
concentrate on most critical elements in formulation
Q Attribute Criteria
Content uniformity If API represents < 25% of final mass
Assay If the API is poor stable
Related substances If API is poor stable
Disintegration In case of BCS I or III
Dissolution In case of BCS II or IV
Loss on drying/ Water If API is hygroscopic
Hardness
If dosage form is coated, and API has poor
compaction properties
Friability
If dosage form is coated, and API has poor
compaction properties

•Tablets are popular for several reasons:
The oral route represents a
convenient and safe
way of drug administration.
Compared to liquid dosage forms, tablets (and
other solid dosage forms) have general
advantages in terms of the chemical, physical
and microbiological stability of the dosage form.
The preparation procedure
enables accurate
dosing of the drug.
O6u, Faculty of pharmacy, Pharmaceutics 3,
Dr.osama elnahas
Tablets are convenient to handle and can be
prepared in a versatile way with respect to their
use and the delivery of the drug.
Finally, tablets can be relatively cheaply mass produced, with robust and
quality-controlled production procedures giving an elegant preparation of
consistent quality.

O6u, Faculty of pharmacy, Pharmaceutics 3,
Dr.osama elnahas
The main disadvantage of tablets as a dosage form is
the problem of poor bioavailability of drugs due to
unfavorable drug properties, e.g. poor solubility, poor
absorption properties and instability in the
gastrointestinal tract.
In addition, some drugs may cause local irritant effects
or otherwise cause harm to the gastrointestinal mucosa

O6u, Faculty of pharmacy, Pharmaceutics 3, Dr.osama elnahas
A common means of
classifying tablets is
based on the drug
release pattern from
the tablets.
Immediate
release
Modified-
release tablets.
the drug is intended to be
released rapidly after
administration, or the
tablet is dissolved in liquid
before intake and thus
administered as a solution.
Prolonged release.
Pulsatile release.
Delayed release.
Immediate-release tablets
are the most common type
of tablet and include
disintegrating, chewable,
effervescent, sublingual and
buccal tablets.

Modified-
release tablets.
Modified-release tablets should
normally be swallowed intact.
The term prolonged-release (controlled
release) tablet is used to indicate that the
drug is released slowly at a nearly
constant rate.
If the rate of release is constant during a
substantial period of time, a zero-order
type of release is obtained, i.e. M = kt
(where M is the cumulative amount of
drug released and t is the release time).

Modified-
release tablets.
For delayed-release tablets the drug is
liberated from the tablet some time after
administration.
After this period has elapsed, the release is
normally rapid.
The most common type of delayed-release
tablet is a gastro-resistant (also known as
enteric coated) tablet, for which the drug is
released in the upper part of the small
intestine after the preparation has passed the
stomach.

Modified-
release tablets.
A pulsatile release is another means to
increase the time period for drug absorption
after a single administration and is
accomplished by releasing the drug in two
or more pulses.

Formulation development:
•Formulation development activities
are:
•Ingredients selection
•Processing selection

Ingredients
•The main ingredients categories are:
•Fillers
•Binders
•Disintegrates
•Lubricants, Glidants and anti-adherents
•Others (Colorant, sweetener, pH modifiers,
flavors, antioxidants, Chelating agents,
Preservatives, Surfactants)

Their role is to ensure that the tableting operation can run
satisfactorily and that tablets of specified quality are
prepared.
Depending on the intended main function, excipients to be
used in tablets are subcategorized into different groups.
One excipient can affect the properties of a powder or the
tablet in a series of ways and many substances used in tablet
formulations can thus be described as multifunctional.

Filler
diluent
Disintegrant Solution binder Dry binder
Glidiant Lubricant Antiadherent

Powder
compaction
characteristics
If API represents more than 20% of final mass, so its
compactability may affect the tableting properties.
Compactability can be defined by various
techniques (Heckel plot, Kawakita analysis),
however the simplest way is determination of
deformation mechanism.
Materials may be classified according to their
deformation mechanism; Plastic, elastic,
fragmentation
Understanding deformation mechanism help in
understanding compression cycle and reworkability
of the formulation.

Mechanism Examples
Elastic Starch, Paracetamol
Plastic Avicel
Fragmentation Sucrose, Dibasic Calcium Phosphate

Powder compaction characteristics
• Simple way to measure deformation
mechanism:
• Mix Drug with 1% Magnesium
stearate for 5 minutes (Blend I)
• Mix Drug with 1% Magnesium
stearate for 15 minutes (Blend II).
• Use 13 mm flat punch to compress
the powder at 1 ton
• Compress (Blend I), hold for 1
second prior to release (sample A).
• Compress (Blend I), hold for 30
second prior to release (Sample B).
• Compress (Blend II), hold for 1
second prior to release (Sample C).
• Store the compressed tablets
overnight to allow equilibrium
• Measure hardness
• A<B Plastic
• A>C Plastic
• C<A<B Plastic
• A=B or C Fragmentation
• A=B=C Fragmentation
• If powder is not compressed, so it
is elastic

Significance of deformation mechanism
•Material with fragmentation pattern: Tablet hardness
is not sensitive to lubricant conc., mixing time,
compression force nor dwell time. However this
material show lower hardness upon rework.
•Materials with plastic pattern: Increase dwell time
results in increase tablet hardness.
•Materials with elastic pattern: Material will rebound
on release of compression force. If bonding is weak,
capping or lamination will occur. Such materials need
plastic filler or wet granulation.

Filler (or diluent)
Tablets normally weigh at least 50
mg.
Therefore, a low dose of a potent drug requires the
incorporation of a substance into the formulation to increase the
bulk volume of the powder and hence the size of the tablet.
Filler is not necessary if the dose of the drug per tablet is high.
possess good technical properties (such as compactability and dilution capacity)
have an acceptable taste cheap
chemically inert non-hygroscopic biocompatible
possess good biopharmaceutical properties (e.g. water soluble or hydrophilic)

Filler (or diluent)
Diluent shall be
chosen based on:
• Final tablet weight
• API characteristics
(solubility,
hygroscopicity,
stability,
compactability)
Soluble diluents are
used to improve
solubility of poorly
soluble API.
Insoluble diluents
shall be used for
soluble API.

Lactose
Is the most common filler in tablets.
Dissolves readily in water
has a pleasant taste, is non-hygroscopic
is fairly non-reactive
shows good compatibility.
Its main limitation
Some people have an intolerance to lactose

lactose
Lactose is a soluble diluent that is
available in different physical forms;
powder, spray dried, agglomerates
prepared by roller compactor.
Lactose undergoes fragmentation
deformation under compression, so
its rework is bit difficult.
Compactability of anhydrous lactose
is higher than lactose monohydrate

lactos
e
Lactose monohydrate is alpha type, where lactose anhydrous
is Beta type.
The molecular structures of α- and β -lactose differ in the
orientation of a hydrogen- and a hydroxyl group on carbon
atom no.1 in the glucose moiety.
β –lactose dissolves faster than α- type.
Spray dried lactose is a mixture of crystalline/ amorphous
lactose 85/15. Amorphous lactose (Mix of & ) is very
hygroscopic, plastic deformable and lack brittleness of
crystalline  lactose.
Roller dried lactose is less hygroscopic.
Amorphous lactose is unstable, and may be converted upon
storage (under high RH) to crystalline lactose. This result in
loss of compressability of lactose spray dried.

Maillard reaction (1ry amine API with B lactose):
High temperature,
humidity and alkaline pH
promote the reaction.
The result is yellow,
brown or black polymer.

Other sugars or sugar alcohols, such as
glucose, sucrose, sorbitol and mannitol, have
been used as alternative fillers to lactose,
primarily in lozenges or chewable tablets
because of their pleasant taste.
Mannitol has a negative heat of solution and
imparts a cooling sensation when sucked or
chewed.

Apart from the sugars, perhaps the most widely used fillers
are powdered celluloses of different types.
biocompatible
Chemically inert
have good tablet-forming Disintegrating properties
They are therefore also used as dry binders and disintegrants
in tablets.
hygroscopicity, may be incompatible with drugs prone to
chemical degradation in the solid state.

Microcrystalline cellulose (Avicel).
•Microcrystalline Cellulose
One of the most famous diluents that was
introduced by FMC in 1960s to overcome
problems associated with lactose. It is available in
several grades that differs according to particle
size and moisture content. MCC is insoluble
hydrophilic diluent that is undergo plastic
deformation by compression.
prepared by hydrolysis of cellulose followed by spray drying.

Final important example of a common filler is
Inorganic substance
dicalcium phosphate dihydrate.
insoluble in water non-hygroscopic
hydrophilic, i.e. easily wetted by water
mainly used in granulation
possesses good flowability
tablet production by direct compaction.

Calcium phosphate
slightly alkaline
May thus be incompatible with drugs
sensitive to alkaline conditions.

Calcium Phosphates
•Insoluble basic
diluent that is used
to improve the
stability of acid-labile
actives. It is available
in different forms
and particle sizes.

Binder adhesive
Added to a drug- filler mixture to
ensure that granules and tablets
can be formed with the required
mechanical strength.

Binder
•Binders are added to tablet formulations to add cohesiveness
to powders, to improve bonding to form granules.
•Binders may be used in dried form in DC techniques, or in
solution in wet granulation.
•Binder in solution is more efficient than dry binders.

Binders can be added to a powder in different ways:
As a dry powder which is mixed
with the other ingredients before
wet agglomeration.
During the agglomeration
procedure, the binder might thus
dissolve partly or completely in
the agglomeration liquid
As a solution which is used as
agglomeration liquid during wet
agglomeration. The binder is here
often referred to as a solution
binder
As a dry powder which is mixed
with the other ingredients before
compaction (slugging or
tableting). The binder is here
often referred to as a dry binder.
Both solution binders and
dry binders are included in
the formulation at relatively
low concentrations, typically
2–10% by weight.

Common traditional solution binders
are starch, sucrose and gelatin.
More commonly used binders today, with
improved adhesive properties, are polymers such
as polyvinylpyrrolidone and cellulose derivatives
(in particular hydroxypropyl methylcellulose).
Dry binders are microcrystalline
cellulose and crosslinked
polyvinylpyrrolidone.(Kollidon)

Binder in formulation of tablets
• Binder solution may be prepared using aqueous or non-aqueous
solvents.
• Aqueous binders provide higher binding than organics.
• Addition of surfactants improve powder wetting and ease granulation
process.
• Binder solution quantity varies 10-35% based on solubility of
fillers/API. Less aqueous binder solution is required for water soluble
fillers/API blend.
• Non-aqueous solvents are used for moisture-sensitive materials or
low-melting point API.
• Non-aqueous solvents include ethanol, methanol, acetone and
Isopropyl alcohol.
• Adequate precautions shall be taken upon usage organic solvents
(usage of explosion-proof drying systems)

Disintegrant
is included in the formulation to ensure that the tablet, when in
contact with a liquid, breaks up into small fragments, which
promotes rapid drug dissolution.
Ideally, the tablet should break up into individual drug particles
in order to obtain the largest possible effective surface area
during dissolution.

The disintegration process for a tablet occurs in two steps.
First, the liquid wets the
solid and penetrates the
pores of the tablet.
Thereafter, the tablet
breaks into smaller
fragments.
De-aggregation directly into
primary powder particles will
set up conditions for the
fastest possible dissolution of
the drug.
Several mechanisms of action of disintegrants have been
suggested, such as swelling of particles, exothermic wetting
reaction, particle repulsion and particle deformation recovery.

1. Disintegrants that facilitate water uptake.
These disintegrants act by facilitating the transport of liquids
into the pores of the tablet, with the consequence that the tablet
may break into fragments..
One obvious type of substance that can promote liquid
penetration is surface-active agents.
It has also been suggested that other substances can promote the
liquid penetration, using capillary forces to suck water into the
pores of the tablet.

2. Disintegrants that will rupture the tablet.
Rupturing of tablets can be caused by swelling of the disintegrant
particles during sorption of water.
However, it has also been suggested that non-swelling disintegrants
can break the tablet and different mechanisms have been suggested.
- recovery of deformed particles to their original shape in contact
with water, i.e. particles which have been deformed during
compaction..

3.Disintegrants by gas production:
A third group of disintegrants functions by producing
gas, normally carbon dioxide
Such disintegrants are used in effervescent tablets and normally
not in tablets that should be swallowed as a solid.

The disintegrant most traditionally used in conventional tablets
is starch, among which potato, maize and corn starches are
commonly used.
The typical concentration range of starch in a tablet formulation
is up to 10%. Starch particles swell in contact with water and
this swelling can subsequently disrupt the tablet.
High-swelling disintegrants are included in the formulation
at relatively low concentrations, typically 1–5% by weight.

Disintegrant Type Common Conc.
Common
Croscamellose sodium Super-disintegrant 0.5-5%
Crospovidone Super-disintegrant 2-5%
Sodium Starch glycolate Super-disintegrant 2-8%
Starch Disintegrant 3-25%
Pre-gelatinized starch Disintegrant 5-10%
Less Common
Alginic acid Disintegrant 1-5%
Calcium alginate Disintegrant < 10%
Hydroxypropyl cellulose-
low substituted
Disintegrant
Magnesium aluminum
silicate
Disintegrant

tablets_part_1.pdf

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