homogenization

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DEFINITION
 Mixing is a unit operation that aims to treat

two or more components initially in an

unmixed or partially mixed state, so that
each unit (participle or molecule of
component) lies as nearly as possible in
contact with each unit of the other particle.
A perfect mix is when this is ideally achieved.

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 This is to have even distribution to ensure even
appearance and homogeneity.

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i. Mixing is an intermediate stage in production /
manufacturing.
ii. Whenever a product contains more than one
component, a mixing or blending state will be
required in the manufacturing process.
iii. It is an integral part in pharmaceutical production
 formulations utilize the following mixing processes.
a. Mixtures of solid particles (powder mixing) e.g.
tablets, capsules, dry powders inhalers etc.
b. Mixtures of miscible liquids e.g. linctuses
c. Mixtures of immiscible liquids e.g. emulsions and
creams
d. Dispersions of solid particles e.g. suspensions

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 They can be categorized into 3 types:
i. Positive mixtures
ii. Negative mixtures
iii.Neutral mixtures

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i. Positive mixtures – This is obtained from materials
which mix spontaneously and irreversibly by
diffusion and tend to form a perfect mix. There is no
input energy required with the positive mixtures.
ii. Negative mixtures – this occurs when components
tend to separate out. If this happens quickly, then
energy must be continuously input to keep the
components adequately dispersed e.g. with
suspension formulation. They are generally more
difficult to mix and maintain.
iii. Neutral mixtures - These are static in behavior i.e.
components have tendency to mix spontaneously or
segregate spontaneously once work has been put to
mix them e.g. powders.

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 Powders
 Powders experience three primary mechanisms

for mixing
i. Convective movement of relatively large portions
of the bed.
ii. Shear mixing which reduces the scale of
convection.
iii. Diffusive movement of individual particles

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 It arises when there is transfer of relatively
large groups of particles from one part of
powder bed to another as might occur when a
mixer blade or paddle moves through the mix.

 It tends to produce a large degree of mixing

fairly quickly

 Mixing does not occur within the group of

particles moving together as a unit and in
order to achieve a random mix extended
mixing time is required.

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 It occurs when a layer of material moves or
flows over another layer.

 It may be due to removal of a mass by convective

mixing creating an unstable shear or slide plane
which causes the powder bed to collapse.

 It may also occur in high shear mixers or

tumbling mixers where the action of the mixer
induces velocity gradient within the powder
bed and hence shearing one layer over
another.

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 When a powder bed is forced to move or flow, it
will dilate by increasing the volume
occupied by the bed due to loosening of the
powder particles and increase in air space.

 Particles tend to fall by gravity through the

viods created. It results in low rates of
mixing.

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 All the 3 mechanisms are likely to occur in a
mixing operation.
 The predominating type depends on

i. the machine used,

ii. The mixing process condition

iii.Flowability of powder

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The mixing mechanisms are:
i. Bulk transport
ii. Turbulent flow
iii.Streamline or laminar flow
iv.Molecular diffusion

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1. Bulk transport
This refers to movement of relatively large
bulk of material being mixed from one
location in the system to another.

For bulk transport to be effective it must result in

rearrangement of various materials being mixed.

Itis accomplished by paddles and revolving

blades which move adjacent volumes of
liquids in different directions thereby
shaffling the system in three dimensions.

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 It is as a result of turbulent fluid flow
characterized by random fluctuation of fluid
velocity at any given point within the system.

 The changing flow characteristics of

turbulence resulst in constantly changing
velocities in different directions.

 In turbulent flow, the fluid has different

instantaneous velocities at different locations at
the same time.

 It can be conveniently visualized as a composite

of eddies of various sizes.

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Fluid flow

 An eddy is defined as a portion of fluid moving as

a unit in a direction contrast to the general flow.
Large eddies tend to break up forming smaller
eddies.

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 This is constantly encountered when highly
viscous material is being mixed.

 It can also occur if stirring is relatively gentle.

 Mixers may also operate by simply stretching the

fluid layers without any significant folding action.

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 The primary mechanism is diffusion resulting
from the thermal motion of the molecules.
Diffusion results in complete mixing.

 The process is governed by ……

dm/dx = -DA/D *de/dx

 Where the rate of transport of mass (dm/dx)

across an interface of area (A) is proportional to
the concentration gradient(de/dx) across the
interface.

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 The rate of intermingling is governed by diffusion
coefficient D which is a function of variables
including fluid viscosity and the size of diffusing
molecules.
 The concentration gradient at the original
boundary is a decreasing function of time
approaching zero as mixing approaches
completion.

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 Segregation is an opposite effect to mixing
i.e. components tends to separate out and
the mixture changes from being random to
non random.

 Care must be taken to prevent segregation after

mixing has taken place.

 Segregation occurs because the mixing

powders are not of monosized spherical
particles but contain particles that differ in
size, shape and density.

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 This means particles tend to behave differently
when moved and hence they separate.

 Particles with similar properties tend to

congregate leading to regions of high
concentration of a particular component.

 Segregation is more likely to occur if

particles are subjected to vibration and if
they have high flowability.

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1. Particle Size Effects
 Difference in particle size is the main cause of

segregation. Smaller particles tend to fall through

the voids of larger particles and move to the
bottom of the mass. This is referred to as
percolation.

 Segregation occurs to a greater extent

when the bed dilates on being disturbed.
This leads to rearrangement e.g. during vibration,
stirring or pouring.

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 During mixing, larger particles will have
greater kinetic energy due to their mass
and hence they move greater distances than
smaller particles.

 This will lead to separation of particles of different

sizes referred to as trajectory segregation.

 Elutriation segregation occurs when very small

particles (dust) tend to be blown upwards when
other particles stumble. These then settle later
on top of coarse particles. The process is also
called dusting out.

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 If particles are of different densities, the more
dense particles will tend to move downwards
even if the particles are of a similar kind.
Trajectory segregation may also occur.

 Effects of density may be potentiated if the more

dense particles are smaller in size.

 The density and size effects may cancel out if the

large particles are more dense.

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 Spherical particles exhibit the greatest effect
and are more easily mixed but they also
segregate more easily and irregularly.

 Middle–shaped particles may become

interlocked thereby reducing the tendency to
segregate once mixing has occurred.

 Non-spherical particles will also tend to have

greater surface area to weight ratio which will
reduce segregation.

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i. Select particular size fractions e.g. by sieving
to remove fines or lumps so as to achieve
drugs and exicipients of same or narrow
particle size range.
ii. Milling of components and size reduction to
reduce the particle size range followed by
sieving to ensure all particles are below 30µm
at which segregation does not occur.
iii. Controlled crystallization during production of
drugs or excipients to give components of a
particular crystal shape or size range.
iv. Selection of excipients which have the same
densities.

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v. Granulation of powder mix (size enlargement) so
that a large number of different particles are
evenly distributed in each segregating unit.
vi. Reducing the extent to which the powder mass
is subjected to vibration or movement after mixing
vii. Use equipment where several operations can
be carried out without transfer of the mix e.g.
mixer-granulator, fluidized bed driers etc

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 When a sufficiently small quantity of micronized
powder becomes adsorbed on the active site
of the surface of a larger carrier particle, the
component exhibit greater resistance to
being dislodged.
 This minimizes segregation and optimizes flow.

Segregation may also occur in ordered mixing if:-

i. The carrier particles vary in size

ii. There is competition for active sites on carrier

particles
iii. There are insufficient carrier particles

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 Doubling up
 When mixing formulations where there is a relatively

low proportion of active ingredients, an even

distribution can be obtained by doubling up.
Steps
 The active ingredient is mixed with equal amount of

excipient or diluent, and then further amount of diluent,

equal to the amount in the mixture is added and mixed.
 The process is continued until all material has been added. It is

appropriate to preblend in a small mixer before transferring to

a larger mixer.
 Care must be taken to avoid over or underfilling which reduces

the efficiency of mixing.

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 The mixer used should be able to produce
appropriate mixing mechanism for the
formulation e.g. diffusive mixing is preferred for
potent drugs and high shear is required to break
aggregates of cohesive materials and ensure mixing at
particulate level.
 The mixer design should be such that its dust
tight, easily cleaned and products can be fully
discharged to prevent the risk of contamination.
 Mixing time should be determined by use of test
samples.
 Static charges are generated during mixing
leading to clumping.
 The equipment should be appropriately earthed
to avoid this.

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Tumbling Mixers
 Tumbling mixers are used for mixing

granules or free flowing powders.

The design includes:
 Double cone mixers
 Twin cone mixtures
 T cone mixtures
 Cube cone mixtures
 Drum mixtures

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 Intermediate bulk containers may be used
as the mixing bowl or to feed the hopper in
the tablet or capsule machine or as a
hopper itself.
 Mixing containers are mounted to enable

rotation about their axis.

 When rotated at correct speed, tumbling

action is obtained.

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1. Shear mixing
It occurs as velocity gradient is produced at the

top layer moving with the greatest velocity and

the velocity reducing as the distance from the
surface increases.
2. Diffusive Mixing
When the bed tumbles, it dilates hence allowing

particles to move downwards under gravity.

High velocity will cause centrifugation and little

speed will lead to insufficient bed expansion and

little shear mixing.

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 Addition of prongs, paddles or rotating bars
will cause diffusive mixing.
 Tumbling mixers are good for free flowing

powders or granules but are poor for

cohesive or poorly flowing powders
 They are used for blending lubricants,

glidants or external disintegrants with

granules prior to tableting.
 They can be used to produce ordered

mixtures

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 It is used to mix and granulate a product
and hence remove the need to transfer the
product between pieces of equipment
thereby reducing the opportunity for
segregation to occur.

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 The centrally mounted impeler blade at the bottom
of the mixer rotates at high speed, throwing the
material towards the mixer wall by centrifugal force.
 The material is forced upwards before dropping back
down towards the centre of the mixer.
 Materials are mixed quickly due to high shear force
and expansion in the bed that allows diffusive
mixing.
 Once mixed, a granulating agent may be added and
granules formed using a slower impeller speed and
actions of side mounted chopper blades.

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 Granulation enhances formation of granules and
is aimed to enhance flow into tableting
equipment.

 Note: Care must be taken to avoid material

fracture. Lubricants which can easily be
overmixed should not be blended in this machine.

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 It can be used to mix powders prior to
granulation in the same batch.
 There is a moving stream of air fed

into the bottom of the shell.

 The body of the powder is fluidized and

mixing is accompanied by circulation

and overtumbling in the bed.

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 The mixers depend on the motion of
the blade or paddle through the
product and hence the main mixing
mechanism is convection.
 Examples include -
 Ribbon mixers
 Planetary mixers
 Nautamixer

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i) Ribbon mixer

 Mixing is achieved by the rotation of helical

blades in a hemispherical trough.

 Dead spots are difficult to eliminate in this type of

mixer. The shearing action forced by the movement
of the blade may be insufficient to break up drug
aggregates.

 The mixer does not mix poorly flowing material and

it is less likely to cause segregation.

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 The blades are mounted on a horizontal
axle by struts and are rotated to circulate
the material to be mixed.
 The mixers may be emptied through parts

in the bottom or by inverting them.

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 It consists of a cylindrical vessel fitted at
the base with a rotating screw which is
fastened to the end of the rotating arm at
the upper end.
 The screw type impeller constantly moves

the batch and conveys it near the top where

it cascades back into the mass.
 The mixer combines convective mixing,

shear and diffusive mixing.

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 Motar and pestle are used for small scale
mixing usually for prescription compounding. A
spatula and sieves may also be used.
 Motor and pestle uses comunition and mixing in a
single operation.
 It is useful when some degree of size reduction is
required e.g. in crystalline materials.
 Blending of powders with a spatula on a tile
or paper (spatulation) is used for small
scale quantities of powders.

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 It is used as an auxiliary blending technique or
when compaction produced by the motar and
pestle technique is undesirable.
 Spatulation is relatively inefficient method of
mixing and hence the principle of geometric
dilution must be employed.
 Sieving is usually employed as a pre or post
mixing method to reduce loosely held
agglomerates and to increase the overall
effectiveness of a blending process.
 Several passes through the sieve are required to
produce a reasonable homogenous mix.

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 Mobile liquids with low viscosity are easy to mix.

 Solid particles are also readily suspended in

mobile liquids though they settle easily when
mixing is discontinued.

 Viscous liquids are difficult to stir but settling of

suspensions does not occur easily

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 They are used for medium scale fluid mixing. The
propeller has angled blades which cause the fluids
to circulate in axial, radial and tangential
directions.
 Off centre mounting discourages formation of
vortex.
 A vortex forms when the centrifugal force imparted
to the liquid by the propeller blades causes it to
back up around the sides of the vessel creating a
depression at the shaft.
 As the speed of rotation increases, air may be
sucked into the fluid by the formation of vortex
causing frothing and possible oxidation.

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 It may be used for more viscous liquids.
 The impellar has 4 flat blades surrounded by
perforated inner and outer diffused rings.
 The rotating impellars draw the liquid into the
mixer head and forces the liquid through the
perforations with considerable radial velocity
sufficient to overcome the viscous drag of the
bulk of the fluid.
 As the fluid is forced through the small
perforations of the diffuse rings at high velocity,
large shear forces are produced.

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 When mixing immiscible liquids and the velocity
is sufficiently high, the shear force produced
enables formation of droplets of stable emulsions
(oil in water or water in oil).
 Very high viscosity liquids cannot be mixed by
this machine.

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 Mobile miscible components of a liquid can
be fed through an inline mixer designed to
cause turbulence in a flowing fluid stream.
 In this case a continuous mixing process is

possible.

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Example of a Dynamic
I n-Line Mixer

Piero M. Armenante ChE702 95

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 Semisolids do not flow easily and hence mixing is
not easy.

 The suitable mixer must have rotating elements

with narrow clearances within themselves and
the mixing vessel wall.

 Most mixers produce a high degree of shear

mixing or diffusion but convection cannot occur.

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 The mixing blade is set off-centre and is carried
on the rotating arm. It therefore travels around
the circumference of the mixing bowl while
simultaneously rotating around its own axis. It
attains double rotation.

 A small clearance between the vessel and the

paddle gives shear force.

 They are sometimes used to mix powders when

wet mass for granulation is required.

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 They are used for ointments and stiff pastes and
depends on two blades which resemble the
Greek letter sigma in shape.

 The clearance between the blocks and the mixing

trough is kept small.

 The mix is usually subjected to further action of a

roller mill or colloid mill so as to rub these
particles to intense shear with very small
clearance between them.

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 Thank you

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