WELCOME

Compression and compaction

GUIDED BY PRESENTED BY
DR. PRAMOD K ANASWARAASHOK KC
ASSOCIATE PROFESSOR M.PHARM 1 ST
SEM
COPS KOZHIKODE

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 CONTENTS
1. Definitions
2. Compression
3. Physics of tablet compression
4. Consolidation
5. Effect of friction
6. Distribution of forces
7. Compaction profiles
8. Solubility

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 DEFINITIONS
Compression is the reduction in bulk volume of material due to displacement of gaseous phase by applied
pressure.
Consolidation is the increase in the mechanical strength of material resulting from particle-particle
interactions.
Compaction can be defined as the compression and consolidation of a particulate solid–gas system as a
result of an applied force, forming a compact but porous mass of a definite geometry.
Transformation of powder into coherent specimen caused by applied pressure is compaction.
Compaction = Compression + Consolidation

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Compressibility is the ability of a material to undergo a reduction in volume as a result of an applied
pressure
Compactibility is the ability of a material to produce tablets with sufficient strength under the effect of
densification
Tabletability is the capacity of a powdered material to be transformed into a tablet of specified strength
under the effect of compaction

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 POWDER COMPRESSION
• It is defined as the reduction in a volume of powder due to the application of forces. It is due to the
surfaces bonds are formed between the particles.
The bonds involved are,
Mechanical interlocking
Inter particulate attraction forces
Solid bridges
• These bonds provide coherence to the powder, that is a compact is formed.

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PHYSICS OF TABLET COMPRESSION
TABLETS:
• Tablets are compressed solid dosage forms consisting of active ingredients and suitable pharmaceutical excipients for
oral administration.
• They may vary in size, shape, weight, hardness, thickness, disintegration and dissolution characteristics and in other
aspects. Tablets constitute about 70-80% of all pharmaceutical dosage forms.
• They are manufactured by
➢ Granulation
▪ Dry granulation : suitable for drugs that are sensitive to moisture and heat.
▪ Wet granulation : suitable for drugs that are stable to moisture and heat.
➢ Direct compression
▪ Powder compression : suitable for drugs that are sensitive to moisture and heat, good flowability and
compressibility.
▪ Crystal compression : suitable for drugs with proper crystal form 7
and good flowability.
Method of Granulation
The wet granulation process is the most conventional technique in the manufacture of tablets and was once
thought to yield tablets that dissolve faster than those made by other granulation methods.
The limitations of this method include
(i) Formation of crystal bridge by the presence of liquid
(ii) The liquid may act as a medium for affecting chemical reactions such as hydrolysis
(iii) The drying step may harm the thermo-labile drugs.
So the method of direct compression has been utilized to yield tablets that dissolve at a faster rate.

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 TABLET COMPRESSION
Equipment for tablet compression
Tablet Press Machine
It is an electro mechanical device that uses compression force to transform powder into tablets of uniform
size and thickness.
Principle
The basic principle behind the tablet compression machine is hydraulic pressure. This pressure is transmitted
unreduced through the static fluid.
Any externally applied pressure is transmitted via static fluid to all the directions in the same proportion.
Types Of Machines For Tablet Compression
* Single station tablet press
* Multi-station tablet press

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SINGLE STATION TABLET PRESS

 A single station tablet press machine is the simplest

tableting equipment.

 It is also called as single punch or eccentric press.

 It can be operated manually or by electric motor

 The compression force of the machine is due to the

upper punch only, and the lower punch remains stationary

during this period.

The single punch tablet press usually produces 60- 85 tablets/min

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PARTS OF THE SINGLE PUNCH MACHINE
i. Hopper: This is the section to put all the material to be compressed either manually or using other
mechanical means.
ii. Die Cavity: This determines both the size and shape of the tablet.
iii. Punches: These machines have upper and lower punches that press the material within the die cavity
into a desired tablet.
iv. Tablet Adjuster: It helps to control the size and weight of the tablet by regulating the amount of
powder intended to compress.
v. Ejection Adjuster: It makes it easy to eject the tablets from the die cavity of the tableting machine.

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 WORKING MECHANISM OF THE SINGLE PUNCH PRESS

The working cycle is as follows

➢ Filling
➢ Weight adjustment
➢ Compression
➢ Ejection
(i) Filling:- This process involves the transfer of granules into position for tablet compression. The upper
die moves upwards and the lower die moves downwards and is responsible for the volume of the die
cavity.
(ii) Weight Adjustment:- The lower punch is raised to the required level in the die to get the required
weight of granules in the punch die cavity. Excess granules are scraped off from the surface of the die
table.
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(iii) Compression:- During this stage, the top and bottom punch come together by pressure within the die to
form the tablet and move between two large wheels called compression rolls. These rolls push the punches
towards the die to form the tablet.
(iv) Ejection:- This process involves removal of tablet from the lower punch die station. In this stage, the
upper punch retracts from the die and rises above the turret table. The lower punch rises in the die, which in
turn pushes the tablet upward to the top surface and out of the cavity.

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ADVANTAGES OF SINGLE PUNCH TABLET MACHINE

In most cases, this machine can be used to make chewable and effervescent tablets.

a) Easy to operate, no need for advanced training.

b) Space saving due to small structure.

c) Reduces weight variations since it uses high pressure.

d) Operates with low noise.

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 MULTI -STATION ROTARY PRESS
 A multi -station press tablet manufacturing machine, also known as rotary machine is one of the most
popular equipment in the pharmaceutical industry due to its high production capacity .
 The name rotary tablet press is due to the rotating tableting assembly .
 In these machines, the rotation speed of the turret and number of stations that determine the production
capacity .
 Used to produce about 8 ,000 to 200 ,000 tablets per hour .

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 WORKING MECHANISM OF A ROTARY TABLET PRESS
The three steps include:
➢ Filling
➢ Compression
➢ Ejection
(i) Filling: The material to be compressed is placed in the fixed hopper and then, it is fed to the several dies
simultaneously.
(ii) Compression: Like in case of the single punch machines, the punches exert the required magnitude of
force to convert powder or granules to tablets.
(iii) Ejection: After full compression, the automatic tablet press machine will withdraw the upper punch as
the lower punch rises. This brings the tablet above the die’s surface.

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 ADVANTAGES OF MULTIPLE STATION TABLET PRESS MACHINE

a) Cost efficient than single punch tablet press.

b) Suitable for continuous operations.

c) Automated systems, hence eliminates most human interventions and thus ensures consistency and accurate

tableting processes.

d) Guarantee independent control of both hardness and weight.

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The steps / process involved in the tablet compression
1. Transitional repacking/particle rearrangement
2. Deformation at the point of contact
3. Fragmentation
4. Bonding
5. Deformation of solid body
6. Decompression
7. Ejection

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 1. TRANSITIONAL REPACKING OR PARTICLE REARRANGEMENT
 The particle size distribution and shape of granules determines the initial packing. In the initial stage of
compression the punch and particle movement occurs at low pressure.
 During this stage, particle moves with respect to each other and smaller particles enter the voids between
the larger particles. As a result, the volume decreases and bulk density of granules increases.
 Spherical particles undergo less rearrangement than irregular particles as spherical particles tend to assume
a close packing arrangement initially.

 To achieve a fast flow rate required for high speed presses the granules is generally processed to produce
spherical or oval granules, thus particle rearrangement and energy expended in rearrangement are minor
considerations in the total process of compression

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Punch and particle
Fines enters the voids
movement at low Rearrangement occurs
of larger particles
pressure

Before After
compression compression
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 2. DEFORMATION AT THE POINT OF CONTACT
 When a stress is applied to a material, deformation (change of form) occurs. If the deformation
disappears completely (return to its original shape) upon the release of stress, it is known as elastic
deformation.
 If the deformation does not completely recover after the release of stress, it is known as plastic
deformation.
 The force required to initiate plastic deformation is known as yield stress.
 When the particles of granulation are so closely packed so that no further filling of the voids can occur,

a further increase of compressional force causes deformation at the point of contact .

 Both plastic and elastic deformation may occur although only one type predominates for a given
material

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 3 FRAGMENTATION
 As the compressional load increases, the deformed particle starts undergoing fragmentation.
 Because of the high load, the particle breaks into smaller fragments leading to the formation of new bonding areas.
 The fragments undergo densification with infiltration of smaller fragments into voids.

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 Fragmentation do not occurs when applied stress
- is balanced by a plastic deformation
- cause change in shape
- cause sliding of groups of particles (viscoelastic flow)

Increase in Formation
High Cracks of new
number of
pressure formation surface area
particle

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 4. BONDING / CONSOLIDATION MECHANISM
 After fragmentation as the pressure increases the formation of new bonds between the particles at the
contact area occurs.
 This leads to increasing mechanical strength of a bed of powder
 There are three theories about the bonding of particles in the tablet by compression

• Mechanical theory

• Inter-molecular force theory

• Liquid film surface theory

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i).Mechanical Theory
 Occurs between asymmetric shaped particles.
 This theory proposes that, under pressure the individual particles undergo elastic/plastic deformation and
that the edges of particles intermesh forming mechanical bond.
Mechanical interlocking is not a major mechanism of bonding in pharmaceutical tableting.

ii).Intermolecular Force Theory

 The molecules at surface of solids have unsatisfied forces which interact with other particle in true contact.
 It states that, under compressional pressure the molecules at the points of true contact between new clean
surfaces of the granules are close enough, so that Vander waal’s forces interact to consolidate the particles
 OH group may also create hydrogen bond between molecules.
eg. Microcrystalline cellulose is to undergo significant hydrogen bonding during tablet compression
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(iii) Liquid – Surface Film Theory
 Due to the applied pressure, the particles may melt (due to lowering of melting point) or dissolve (due to
increased solubility).
 A thin liquid film form, which helps to bond the particles together at the particle surface.
 Many pharmaceutical formulations require a certain level of residual volume of moisture to produce high
quality tablets.
 The energy of compression produces melting of solutions at the particles interface followed by subsequent
solidification or crystallization thus in the formation of bonded surfaces.
 This is the major bonding mechanism involved in the tablet compression.

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 5.DEFORMATION OF THE SOLID BODY

When applied pressure is increased, bonded solid is consolidated towards a limiting density by plastic or
elastic deformation.
6. DECOMPRESSION
 As the applied force is removed, a set of stresses within the tablet gets generated as a result of elastic
recovery.
 The tablet must be mechanically strong enough to accommodate these stress, otherwise the tablet structure
failure may occur.
 If the degree and rate of elastic recovery are high, the tablet may cap or laminate.
 If the tablet undergoes brittle fracture during decompression, the compact may form failure as a result of
fracturing of surfaces.
 Tablets that do not cap or laminate are able to relieve the stresses by
plastic deformation. 28

"The tablet failure is affected by rate of decompression (machine speed).

 7. EJECTION
 As the lower punch raises and pushes the tablet upwards, there is a continued residual die wall pressure
and considerable energy may be expanded due to die-wall friction.
 Three forces are necessary to eject a finished tablet
i. Peak force required to initiate ejection.
ii. Small force required to push tablet up to die wall
iii. Decline force as tablet emerges from die

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CONSOLIDATION
An increase in the mechanical strength of material resulting from particle or particle interaction is called
consolidation.
Consolidation process is of two types:
1. Cold welding
When the surface of two particles approach each other closely enough, their free surface energies result in
attractive force, this process known as cold welding.
2. Fusion bonding
Multiple point contacts of particles upon application of load produces heat which causes fusion or melting.
Upon removal of load it gets solidified & increase the mechanical strength of mass.

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CONSOLIDATION MECHANISM
 Mechanical theory
 Inter-molecular force theory
 Liquid film surface theory

FACTORS AFFECTING CONSOLIDATION

Both cold and fusion welding, the process is influenced by several factors like
❖Chemical nature of the materials
❖Extent of the available surface
❖Presence of surface contaminants
❖Inter-surface distances
❖Degree and type of crystallinity
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i Chemical nature of materials
 The type and degree of crystallinity in a material influences its consolidative behaviour under applied
force.
 Substances possessing the cubic lattice arrangement were tableted more satisfactorily than those with a
rhombohedral lattice.
ii. Extent of available surface
 The compressional process is affected by the extent of available surface.
 When a powder mass is subjected to increasing compressional force, there is initial particle fracture, which
gives rise to increased surface area(O to A).
 At the point A, particles re-bonding becomes dominant factor, and from then on surface area decreases
unless tablet lamination begins.

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iii. Presence of surface contaminants
The compressional process is affected by the extent of presence of surface contaminant.
For example, lubricants such as magnesium stearate form weak bond, so that over lubrication or over-
mixing of lubricant into the tableting mass, results in a continuous coating of the tablet, and hence in some
cases weak tablets are formed.

iv. Inter-surface distance

At the low level of external forces, molecular and electrostatic forces are cause the attraction between
individual particles.
Van Der Waal's forces however may exert a significant effect at distance upto 100nm, so that once an
agglomerate of particles has been formed, they may serve to prevents its breakdown

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 Various forces involved in Tablet compression
1. Frictional Forces
2. Distribution forces
3. Radial force
4. Ejection force

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1.FRICTIONAL FORCES / EFFECT OF FRICTION
• Frictional forces are two types:
i. Inter-particulate friction forces occur due to particle - particle contact and it is more significant at low
applied load.
It is expressed as µi (coefficient of inter particulate friction)
These forces are reduced by using Glidants.
Eg: Colloidal silica (fumed silica).

ii. Die wall friction forces occur due to material pressed against die wall , and it is dominant at high applied
load.
It is expressed as µw (coefficient of die- wall friction.)
These forces are reduced using Lubricants.
Eg: Magnesium stearate 35
2. DISTRIBUTION FORCES
• Most investigations of fundamentals of tableting have been carried out on single punch press or even
isolated dies and punches with hydraulic press.
• When force is being applied to top of a cylindrical powder mass, the following basic relationship applies,
since there must be an axial (vertical) balance of forces. FA = FL + FD
FA = Force applied to upper punch
FL = Force transmitted to lower punch

FD = reaction at die wall due to friction at surface

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• Because of this inherent difference between the force applied at the upper punch and that affecting material
close to the lower punch, a mean compaction force, FM, has been proposed

FA + FL
FM =
2

FA= Force applied to upper punch

FL= Force transmitted to lower punch
FM = Mean force

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3. RADIAL FORCE
• As compressional force is increased, any repacking of tableting is completed forming a single body mass.
• Classical friction theory can be applied to obtain a relationship between axial frictional force FD and radial
force FR as

FD = µW x FR

where µW is coefficient of die wall friction.

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4. EJECTION FORCE
 Radial die wall forces and die wall friction also affects the ease with which the compressed tablet is
ejected from the die
 The force necessary to eject the finished tablet is known as ejection force.
Three forces are necessary to eject a finished tablet
i. Peak force required to initiate ejection.
ii. Small force required to push tablet up to die wall
iii. Decline force as tablet emerges from die
 Variation in this pattern also occurs in ejection force when lubrication is inadequate and/or slip-stick
conditions occurs between tablet and die wall.

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 PROPERTIES OF TABLET INFLUENCED BY COMPRESSION
1. Density And Porosity
 The apparent density of a tablet is exponentially related to applied pressure or compressional force until the
limiting size of the material is achieved.
D = m/V
D - Density of particles, m - mass of powder ,V - Volume
 As compressional force increases, the density of tablet also increases as a result of decrease in bulk volume.
 As the porosity and apparent density are inversely proportional, the plot of porosity against log of
compression force gives linear plot with a negative slope.

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2.Hardness & Tensile strength
 A measure of the ability of a material to withstand longitudinal stress, (greatest stress) that the material can
stand without breaking.
 There is a linear relationship between tablet hardness & the logarithm of applied pressure , except at high
pressure of granules
 The tensile strength of crystalline lactose is directly proportional to the compressional force i.e. Increase in
the compressional force increases the strength of the tablet.

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3. Specific surface area
Specific surface area is the surface area of 1 gm material. Specific surface area initially increases to a maximal value as
the compressional force increases, indicating the formation of new surface due to fragmentation of granules. Further
increase in force produce a progressive decrease in surface area due to bonding of particles

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4. Disintegration
 Usually as applied pressure used to prepare a tablet is increased, disintegration time increases
(lactose/aspirin alone).
 Frequently, there is exponential relationship between disintegration time and pressure (Aspirin-Lactose).
 In some formulations, there is minimum value when applied pressure is plotted against log of disintegration
time.

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 5. Dissolution

The effect of applied pressure on dissolution rate may be considered from viewpoint of disintegrating and
non disintegrating tablets, For a conventional tablet (uncoated) dissolution depends on
a. Temperature
b. The properties of the API
c. The properties of the excipients
d. Properties of solvent etc.
 The effect of applied pressure on dissolution of disintegrating tablet is difficult to predict.
 If fragmentation of granules occurs during compression, the dissolution is faster as the applied pressure is
increased, because of increase in specific surface area.
 If bonding of particle predominantly occurs during the compression, then it decreases the dissolution.

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 FACTORS AFFECTING THE STRENGTH OF TABLETS
 Particle size
 Moisture content
 Lubricants
 Applied pressure
 Binders
 Entrapped air
 Porosity
 Particle shape

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1. PARTICLE SIZE
A decrease in particle size resulted in increase in tablet strength, the general equation is
Fc =K×d²
Where, k - constant Fc - hardness of compact , d - diameter of particle

2. APPLIED PRESSURE
At higher forces due to fragmentation, new surfaces are formed causing an increase in surface area. hence
more area is available for bond formation, hence more will be hardness of the compact.
➢ According to Balshin equation,
Fc = Fco × Vr
Where, Fco - strength of tablet , Vr - relative volume

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3.MOISTURE CONTENT
 A small proportion of moisture content is desirable for the formation of a coherent tablet.
 Several effects seen by the presence of moisture content are
Die wall lubrication,
Inter-particulate lubrication
 At low moisture content, there will be increase in die wall friction so hardness will be poor.
 At high moisture level, the die wall friction is reduced owing to lubricating effect of moisture.
Further increase in moisture content, there will be decrease in compact strength due to reduction in inter-
particulate bonds

4. POROSITY
➢Large size particles subjected to light compression will produce highly porous and low tablet strength.

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5. LUBRICANTS
 Lubricants assist particle movement by reducing particle - die wall friction.
 The lubricants is spread over the surface of particles and hence reduces the bonding between the particles.
 It has been reported that increase in the quantity of lubricant resulted in reduction of the mechanical
strength of compressed tablets.
 Eg: Stearic acid, Magnesium stearate, Calcium stearate, Boric acid, etc.,

6. BINDERS
 It is the material added to the formulation to improve the mechanical strength of a tablet.
 Addition of more binder increases elasticity, which can decrease the tablet strength because of breakage of
bonds as compaction pressure is increased.
 Eg: Gelatin, Cellulose derivatives, Polyvinyl pyrrolidine, Starch, etc.,

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 COMPACTION PROFILES
• Many attempts have been made to minimize the amount of applied force transmitted radially to the die
walls. All such studies lead to characteristic curves called as compaction profiles.
• The plot of radial pressure against axial pressure is called compaction profile.
• When the elastic limit of the material is high, elastic deformation may make the major contribution and on
removal of the applied load, the extent of elastic relaxation depends on the value of material modulus of
elasticity (Young’s modulus)
• Lower the modulus, higher will be elastic relaxation, there will be the risk of structural failure.
• Higher modulus results in a small dimensional change on decompression hence lesser risk of structural
failure.
In the compaction cycle, two forces are considered
1. Axial force: This vertical component is applied by the upper punch during compression.
2. Radial pressure: This is the horizontal component observed in the die wall, when the powder 49

mass attempt to expand in the die.

Compression Phase:
 OA- Represents repacking of granules or powders.
 AB Represents elastic deformation which continues up to B (elastic limit)
 BC Represents plastic deformation and brittle fracture.
 Point C indicates the maximum compression force.
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Decompression phase:
 CD-Represents elastic recovery on the removal of applied force.
 DE- Represents recovery from plastic deformation
 E- Represents residual force, which holds the compact in the sides of the die.
 Ejection force must be greater than residual force

Types of compaction profiles

1. Force-displacement profile
2. Force-time profile
3. Die wall force profile

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 1. FORCE-DISPLACEMENT PROFILES
1.The relationship between upper punch force and upper punch displacement during compression, referred to
as force-displacement profile, and it is used to derive information on the compression behavior of a
powder and to predict its tablet forming ability.
2.The area under a force-displacement curve represents the work or energy involved in the compression
process.

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3. Different procedures have been used to analyze the curves. One suggested approach is based on the division of the
force-displacement curve into different regions (denoted El, E2 and E3 in Figure)
4. It has been suggested that the areas of El and E3 should be as small as possible if the powder will perform well in a
tableting operation and give tablets of a high mechanical strength.
5. An alternative proposed approach is based on mathematical analysis of the force displacement curve from the
compression phase,

NWC = GWC - WER

GWC= Wf + Wp + We + Wfr
NWC = net work of compaction
WER = work of elastic relaxation
Wp = work of plastic deformation
Wfr = work of fragmentation
GWC = gross work of compaction
Wf = work against friction
Wc = work of elastic deformation
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6. Force-displacement curves have some use in pharmaceutical development as an indicator of the tablet
forming ability of powders, including the assessment of the elastic properties of materials
7. It can also be used to monitor the compression behavior of a substance in order to document and evaluate
reproducibility between batches.
8. The energy applied to the powder during compaction can be calculated from the area under the force-
displacement curve.

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 2. FORCE- TIME PROFILE
Compression force-time profiles are used to characterize the compression behaviour of the active
ingredients and excipients.
On a rotary tablet press, the force-time curves are segmented into 3 phases
a) Compression phase: Horizontal and vertical punch movement. Compression is the process in which
maximum force is applied on powder bed in order to reduce its volume
b) Dwell phase: Only horizontal punch movement. When compression force reaches a maximum value, this
maximum force is maintained for prolonged period before decompression. The time period between the
compression phase and decompression phase is known as Dwell time.
c) Decompression phase: Both punches moving away from upper and lower surfaces. Removal of applied
force on powder bed

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 Compression phase is small for powders having high density (low volume due to less void spaces).
Eg: Dicalcium phosphate dihydrate.
 Compression phase is large for powders having low density (more volume due to more void spaces).
Eg: Microcrystalline cellulose.
 Plastic materials show a decrease in force over dwell time, in contrast, a plateau is obtained for brittle
materials.
 The dwell phase coefficient can be used to measure the plasticity of a substance mixture tablet is within the die

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Compression event is divided into series of time periods

 Consolidation time: Time period to reach maximum force

 Dwell time: Time at maximum force

 Contact time: Time for compression and decompression

 Ejection time: Time during which ejection occurs

 Residence time: Time during which the formed tablet is within the die

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 3. DIE WALL - FORCE PROFILE
During tableting, friction arises between the material and the die wall and also between the particle
(inter-particulate friction).
Internal friction is significant only during particle slippage and rearrangement at low applied pressures.
The coefficient of frictions related to tableting processes are,
a). Static friction (force required to initiate sliding)
b). Dynamic friction (force required to maintain sliding between two surfaces)
Static friction ( µ1 ) = maximum axial frictional force/ maximum radial force.
Dynamic friction ( µ2 ) = ejection force/ residual die wall force.
Lubrication ratio (R value) is the ratio of the maximum lower punch force to the maximum upper
punch force.

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 The die wall force reaches a maximum just after the maximum upper and lower force
and a constant residual value after upper and lower punch forces become zero. When the ejection process
starts, it increases again.
 The residual die wall force is the average of values in the constant region at zero upper punch force.
 The difference of displacement between upper and lower punch gives a measure of the tablet area contact
with the die wall.

The high die wall force during ejection is a sign of adhesion of powders to the die

Applications of compaction profiles

• These can be used to monitor the compaction cycle.

• Provide information regarding the radial transmission of applied force to the die wall.

• Helps in calculating ejection force and lubricant requirements. 59

• Compaction profiles give good assessment of elastic component of the powder

SOLUBILITY
Solubility is defined as amount of solute that can be dispersed molecularly in the given amount of solvent to
give a homogenous mixture under standard conditions of temperature, pressure and pH.
Test for solubility is used to identify the purity of the drug substance.

IMPORTANCE OF SOLUBILITY
 Therapeutic efficacy of a drug depends upon bioavailability and ultimately depends upon solubility.
 Solubility is one of important parameter to achieve desired concentration of drug in systemic circulation.
 Only 8% of new drug candidates have high solubility and high permeability.
 40% of drugs of new drug entities are poorly water soluble.

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 Method of determination of solubility
 An excess powder is added in the solvent to achieve the saturated solubility and constant stirring is given
for long duration at required temperature till the equilibrium is achieved.
 There should be few amount of undissolved solute should be present in order to ensure that the solvent is
saturated.
 The aliquot of the saturated solution is taken separated from the undissolved solute by specific method.
 Generally speaking, filtration is the common method employed for most of the studied

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Terms Expression of solubility Part by volume of solvent
required to dissolve 1 part by weight of solute

Very soluble Less than 1

Freely soluble From 1 to 10
Soluble From 10 to 30
Sparingly soluble From 30 to 100
Slightly soluble From 100 to 1000
Very slightly soluble From 1000 to 10.000

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 FACTORS AFFECTING SOLUBILITY

1. Solubility of solids in liquids

Temperature
Particle size
Molecular structure modifications
Common ion effect
Effect of complex formation
Effect of surfactants

2 Solubility of liquids in liquids

Complete miscibility
Practically immiscible
Partially miscible

3.Solubility of gases in liquids

Effect of pressure
Effect of temperature
Salting out
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Effect of chemical reactions
 BIOPHARMACEUTICAL CLASSIFICATION SYSTEM
BCS is a scientific framework for classifying drug substances according to their aqueous solubility and their
internal permeability

Class solubility permeability Absorption pattern example

I High High Well absorbed Diltiazem

II Low High Variable Nifedipine

III High Low Variable Insulin

IV Low Low Poorly absorbed Taxol

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ABSOLUTE OR INTRINSIC SOLUBILITY
It is defined as the maximum amount of solute dissolved in a given solvent under standard conditions of
temperature, pressure and pH.

TECHNIQUES OF SOLUBILIZATION
Solubilization is the technique by which the desired solubility of a poorly water-soluble substance is
achieved.
Water is the most commonly used solvent in pharmaceutical liquids

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SOLUBILITY ENHANCEMENT TECHNIIQUES
A. Pharmaceutical approaches
1.pH Adjustments
(a) Salt formation.
(b) Addition of buffers to the formulation.
2. Cosolvency
3. Complexation
4. Surface active agents
5. Hydrotropism
6. Micronization
7. Solid solutions
B. Chemical modifications
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 A. Pharmaceutical Approaches
1.pH Adjustments
 Most of the drugs are either weak acids or weak bases.
 The aqueous solubility of a weak acid or a weak base is greatly influenced by the pH of the solution.
 The solubility of a weak base can be increased by lowering the pH of its solution whereas the solubility of a
weak acid can be improved by increasing the pH.
 pH adjustment for improving the solubility can be achieved in two ways
(a) Salt formation.
(b) Addition of buffers to the formulation.
 Eg. Gatifloxacin is insoluble in water at higher pH but the same drug get solubilized at the lower pH and
attains maximum solubility below the pH of 5.
Hence the parenteral preparation of Gatifloxacin is formulated at the pH of 3.5 to 5.5. 86
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 2. Cosolvency
 Cosolvency is the technique of increasing the solubility of poorly soluble drugs in a liquid by addition
of a solvent miscible with the liquid in which the drug is also highly soluble.
 Cosolvents such as ethanol, glycerol, propylene glycol or sorbitol decreases the interfacial tension or alter
the dielectric constant of the medium and increases the solubility of weak electrolytes and non-polar
molecules in water.
Eg: Formulation of Diazepam injection using Propylene glycol as cosolvent.

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3. Complexation
 In certain cases, it may be possible to increase the solubility of a poorly soluble drug by allowing it to
interact with a soluble material to form a soluble intermolecular complex.
 It is however essential that the complex formed is easily reversible so that the free drug is released readily
during or before contact with biological fluids.

 Eg. 1. Interaction of Iodine with Povidone to form water soluble complex

2. preparation of Itraconazole injection by forming inclusion complex of Itraconazole with Hydroxy
propyl beta cyclodextrin.

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 4. Surface active agent
 A surface active agent is a substance which reduces the interfacial tension between the solute and the
solvent to form thermodynamically stable homogeneous system.
 The mechanism involved in this solubilization technique involves micelle formation and due to
formation of stable system it is widely used in pharmaceutical formulations.
 When a surfactant having a hydrophilic and a lipophilic portion is added to a liquid, it first accumulates
at the air/solvent interface, further addition leads to its dispersion throughout the liquid bulk.
 At a certain concentration known as the Critical Micelle Concentration (CMC), the dispersed surfactant
molecules tend to aggregate into groups of 100 to 150 molecules known as micelle.
 Eg: Fat soluble vitamins A, D, E and K, antibiotics like Griseofulvin and Chloramphenicol and
analgesics such as Aspirin and Phenacetin have been solubilized by using surface active agents.

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5. Hydrotropism
Hydrotropism is the term used to describe the increase in aqueous solubility of a drug by the use of large
concentrations (20% to 50%) of certain additives.
 The exact mechanism for hydrotropism is not clear although complexation, solubilization or cosolvency
have been suggested as the probable mechanisms.
 Hydrotropism is rarely applied to pharmaceutical formulations, as the increase in aqueous solubility is
generally inadequate.
 Eg: Increase in solubility of Caffeine and Theophylline by addition of Sodium benzoate and sodium
salicylate respectively.

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6. Micronization
 Surface area and particle size are inversely related to each other. Smaller the drug particle, larger the surface area and
greater is the solubility.
 A decrease in particle size achieved through micronization, will result in higher solubilization of drug.
 Eg: Micronization of poorly aqueous soluble, but non-hydrophobic drugs such as Griseofulvin and Chloramphenicol
results in enhanced solubility

7. Solid Solutions
 Solid solutions are prepared by melting of physical mixture of solute, a poorly water soluble drug and solid
solvent, a highly water soluble compound or polymer followed by rapid solidification.
 Solid solutions are also called as molecular dispersions or mixed crystals.
 Eg: Griseofulvin from Succinic acid solid solution dissolves 6 to 7 times faster than pure Griseofulvin and
Digitoxin-PEG 6000 solid solution showed enhanced solubility. 72
B.Chemical Modification
 Solubility of a substance can be improved by chemically modifying the substance.
For example,
 Aqueous solubility can be improved by increasing the number of polar groups in a molecule.
 Also by salt formation; for instance, alkaloids are poorly soluble in water whereas alkaloidal salts are
freely soluble in it.
 A molecule may be modified to produce a new chemical entity or prodrug.
 Eg: The aqueous solubility of Chloramphenicol sodium succinate is about 400 times greater than that of
Chloramphenicol.
 Prodrugs, however, must revert to parent molecule after administration.

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Previous year questions
Essays
1. Explain the physics of tablet compression ( July 2019)
2. Explain the compression and compaction in tablet ( feb – 2022)
Short notes
3. Discuss the physics of tablet compression ( April 2018)
4. Explain the physics of tablet compression (2019 march)
5. Effect of friction influencing the compression of tablet (2019 march)
6. Explain the properties of tablets influenced by compression ( 2020 – march)
7. Physics of tablet compression ( January 2021)
8. The compaction profiles in tablet formulation ( November 2021)
9. Explain the physics of tablet compression ( April 2023)
10. Explain in detail about 74

a). Effect of friction b). Solubility

9. Explain the physics of consolidation and distribution of forces
REFERENCE
1. Lachman/Lieberman's. The theory and practice of industrial pharmacy, fourth edition, CBS publishers
&distributors, page No: 467-479
2. Mohan S. Compression physics of pharmaceutical powder a review.[cited 2023
Feb12]Availablefrom:https://www.academia.edu/6658951/COMPRESSION_PHYSICS_ OF
PHARMACEUTICAL POWDERS A REVIEW
3. Compression Physics in the Formulation Development of Tablets, a review article by Sarsvatkumar Patel,
February 2006

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THANKS

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