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Mixing
– Chapter 5
There are very few pharmaceutical products that contain only one
component. In the vast majority of cases several ingredients are
needed so that the required dosage form functions as required.
If, for example, a pharmaceutical company wishes to produce a
tablet dosage form containing a drug which is active at a dose of 1
mg, other components (e.g. diluents, binders, disintegrants and
lubricants) will be needed both to enable the product to be
manufactured and for it to be handled by the patient.
Whenever a product contains more than one component a mixing or
blending stage will be required in the manufacturing process.
Importance of mixing
List of products that invariably utilize mixing processes:
Tablets, capsules, sachets and dry powder inhalers -
mixtures of solid particles (powder mixing)
Linctuses - mixtures of miscible liquids
Emulsions and creams - mixtures of immiscible liquids
Pastes and suspensions - dispersions of solid particles.
Importance of mixing
Theoretical definition:
an operation in which two or more components in separate or
roughly mixed conditions are treated, so that each particle lies as
nearly as possible in contact with a particle of the other ingredients
>>> if this is achieved, it produces a theoretical “ideal” situation, i.e.
a perfect mix. This situation is not normally practicable.
Objective of mixing:
To obtain mixture that when divided into subunits, 1 each subunit will
contain the same quantity of a given component and 2 the same
ratio of components in the entire mixture.
Definition and objective of mixing
To simplify the discussion of the principles of mixing, we will be
considering a system consisting of equal quantities of two
constituents A (white squares) and B (black squares) of the same
size and shape.
Before mixing starts the system may be represented by the
following figure which shows the particles in a completely
segregated state.
Complete segregation (unmixed)
The mixing process
The theoretical end point of mixing is the formation of a perfect mix where
each particle lies adjacent to a particle of the other component.
The statistical probability of achieving such a perfect mix is so minute that
the best attainable mix, regardless of the method of mixing or time of
mixing, is a random mix.
An ideal or “perfect” mix
A random mix
The mixing process
Ideal (perfect) mixing is in accordance with the previous
theoretical definition of mixing, while random mixing is not.
However, random mixing can achieve the objective of mixing
depending on the final unit dose size.
In contrast to the ideal mixing, random mixing can be
achieved practically.
The mixing process
Segregation is the opposite effect to mixing, i.e. components
tend to separate out.
Segregation happens during or after mixing (due to handling or
pouring).
This is very important in the preparation of pharmaceutical
products, because if segregation occurs, a mix may change
from being random to being non-random, or a random mix may
never be achieved.
Segregation
Segregation arises because powder mixes encountered
practically are not composed of mono-sized spherical particles,
but contain particles that differ in size1, shape2 and density3.
These variations mean that particles will tend to behave
differently when forced to move and hence, tend to separate.
Particles exhibiting similar properties tend to congregate
together, giving regions in the powder bed which have a higher
concentration of a particular component.
Segregation
1. Scale of scrutiny
2. % of the active ingredient
3. Particle size
4. Particle size distribution
5. Particle shape
6. Particle density
7. Mixing time
Factors affecting mixing
1. Scale of scrutiny
Often a mixing process produces a large 'bulk' of mixture that is
subsequently subdivided into individual dose units (e.g. a tablet,
a capsule) and it is important that each dosage unit contains
the correct amount/concentration of active component(s).
It is the weight of the dosage unit that dictates how closely the
mix must be examined/analysed to ensure it contains the
correct dose/concentration.
This weight is known as the scale of scrutiny and is the amount of
material within which the quality of mixing is important.
Factors affecting mixing
1. Scale of scrutiny
For example, if the unit weight of a tablet is 200 mg then a 200
mg sample from the mix needs to be analysed to see if mixing
is adequate; the scale of scrutiny is therefore 200 mg.
If a larger sample size than the scale of scrutiny is analysed this
might mask important micro-nonuniformity.
This may lead to the acceptance of an inadequate mix
(see example in next slide)
Factors affecting mixing
1. Scale of scrutiny
Let’s imagine that the aim is a 50% drug (grey)/ 50% excipient
(white) mixture.
Factors affecting mixing
In total 400 particles: 200 particles grey, 200
white (Adequate mixing – 50% drug/50%
excipient).
Within the red block however: 6 particles
are white and 19 are grey (24% excipient
/76% drug Inadequate mixing!!)
Within the green block: 6 particles are grey
and 19 are white (24% drug/76% excipient-
Inadequate mixing!!)
1. Scale of scrutiny
In conclusion:
As the weight of the dosage unit is increased while fixing other
parameters (such as percentage of the active ingredient)
achievement of adequate mixing will be easier. This is
because the size of the scale of scrutiny will increase.
Example: it is easier to achieve more homogenous mixing
for 1000 mg tablets, than for 100 mg tablets (both
containing the same mixture).
Factors affecting mixing
Factors affecting mixing 2. % of the active ingredient
As the percentage is decreased the mixing process becomes
more difficult. Potent drugs with percentage less than 1% present
mixing problems.
To improve mixing for potent drugs:
Geometric (serial) dilution.
Factors affecting mixing
3. Particle size
Reduction of particle size will increase the number of particles
per dosage unit and lead to improvement in achieving
homogenous mixing.
However, too much size reduction would lead to particle
agglomeration due to the increase cohesion that occurs with
smaller particle. This would reduce the ease of mixing.
Factors affecting mixing 4. Particle size distribution: A. In case of broad particle size distribution: the smaller particles occupy
interstices between the larger particles, creating a more densely
packed powder. Densely packed powder usually flows with difficulty.
Accordingly, the narrower the particle size distribution the better the
flow and the easier the mixing.
Narrow particle
size distribution
Less densely
packed powder
Good flow
Easy mixing
Broad particle size
distribution
More densely
packed powder
Bad flow
Difficult mixing
Factors affecting mixing 4. Particle size distribution:
B. Wide particle size distribution can lead to segregation during or after
mixing. Two most common types of segregation: percolation
segregation and trajectory segregation.
I. Smaller particles tend to fall through the voids between larger
ones and so move to the bottom of the mass. This is known as
percolation segregation.
Factors affecting mixing 4. Particle size distribution: II. During mixing, larger particles will tend to have greater kinetic
energy imparted to them (owing to their larger mass) and
therefore move greater distances than smaller particles before
they come to rest. This may result in the separation of particles
of different size, an effect referred to as trajectory segregation.
Factors affecting mixing 5. Particle shape:
Good powder flow can lead to good mixing, but also segregation
(demixing).
Spherical particles:
→ optimum flow: good mixing, but possible segregation.
Interlocking shape (irregular) or fibrous configuration or needle-like
shapes:
→ poor flow: more difficult to mix, but less segregation once mixing
as occurred.
Size reduction of these shapes can be useful in order to change
the shape into more rounded ones.
Factors affecting mixing
Factors affecting mixing 6. Particle density
If components are of different density, the more dense material
will have a tendency to move downwards even if the particle
sizes are similar.
Trajectory segregation may also occur with particles of the
same size but different densities, owing to their difference in
mass.
Often materials used in pharmaceutical formulations have
similar density values and density effects are not generally too
important.
Factors affecting mixing
7. Mixing time
1. Non-segregating mixes will improve with continued increases in
mixing time.
2. This may not, however, occur for segregating mixes, where
there is often an optimum mixing time.
This is because the factors causing segregation generally
require longer to take effect than the time needed to
produce a reasonable degree of mixing. It is therefore
disadvantageous to prolong the mixing time beyond an
optimum point.
Factors affecting mixing How segregation can be minimized?
1. Achieving drug and excipients of the same narrow particle size range
either by:
Selection of particular size fractions for all components.
Milling of coarser components.
2. Selection of excipients which have a density similar to the active
component.
3. Selection of an optimum mixing time.
4. Reducing the extent to which the powder mass is subjected to vibration or
movement after mixing.
Mechanism of powder mixing
There are three main mechanisms by which powder mixing
occurs:
1. Convection.
2. Shear.
3. Diffusion.
1. Convection (macroscopic mixing)
It happens when there is the transfer of relatively large groups of
particles from one part of the powder bed to another, as might
occur when a mixer blade or paddle moves through the mix, for
example.
This type of mixing contributes mainly to the macroscopic mixing of
powder mixtures and tends to produce a large degree of mixing
fairly quickly.
Mixing does not, however, occur within the group of particles moving
together as a unit, and so in order to achieve a random mix an
extended mixing time is required.
Mechanism of powder mixing
Mechanism of mixing for powders
1. Convection
Mechanism of mixing for powders
2. Shear (macroscopic mixing)
Shear mixing occurs when a 'layer' of material moves/flows
over another 'layer'.
This might be due to the removal of a mass by convective
mixing creating an unstable shear/slip plane, which causes the
powder bed to collapse.
Mechanism of mixing for powders
3. Diffusion (microscopic mixing)
When a powder bed is forced to move or flow it will 'dilate', i.e. the
volume occupied by the bed will increase. This is because the powder
particles will become less tightly packed and there is an increase in
the air spaces or voids between them. Under these circumstances
there is the potential for the particles to fall under gravity, through the
voids created.
Mixing of individual particles in this way is referred to as diffusive mixing.
Shear and convective mixing can quickly produce a rough mix but
local groups of particles may remain unseparated unless subjected to
diffusive mixing.
Mechanism of mixing for powders 3. Diffusion (microscopic mixing)
Ordered mixing It would be expected that a mix comprised of very small and
much larger particles would segregate because of the size
differences.
Sometimes, however, if one powder is sufficiently small
(micronized) it may become adsorbed on to the 'active sites' on
the surface of a larger 'carrier' particle and exhibit great
resistance to being dislodged.
The phenomenon is referred to as ordered mixing.
This has the effect of minimizing segregation while maintaining
good flow properties.
Ordered mixing Order mixing, occurs to a certain extent in every pharmaceutical powder
mix, owing to interactions and cohesive/adhesive forces between
constituents. However, it is most likely to occur when smaller particles exist.
Pharmaceutical mixes are therefore likely to be partly ordered and partly
random, the extent of each depending on the component properties.
With an ordered mix it may be possible to achieve a degree of mixing which
is superior to that of a random mix, which may be beneficial for potent drugs.
Note: although ordered mixes can reduce or prevent segregation, segregation
may still occur!
Ordered mixing
Example: Dry powder inhaler formulations use ordered mixing to deliver
drugs to the lungs.
Drug and carrier are mixed to produce an ordered mix.
In this case the drug needs to be in a micronized form (generally <5 µm) in
order to reach its site of action.
The carrier (generally α-lactose monohydrate) has a median size generally
between 30-150 µm.
The powder flows easily out of the inhaler (due to size of the carrier particles)
Once liberated from the inhaler de-aggregation of the drug-carrier
aggregates occurs.
Design
Tumbling mixers are commonly used for
the mixing/blending of granules or free-
flowing powders.
There are many different designs of
tumbling mixer, e.g. double-cone mixers,
twin-shell mixers, cube mixers, Y-cone
mixers and drum mixers.
Tumble mixer can be with or without
agitator mixing bar (or blade)
Tumbler mixers
Mixing containers are generally mounted so that they can be
rotated about an axis.
V-shape blenders(to right) and Double cone (to left)
Tumbler mixers
Mechanisms of mixing
When operated at the correct speed, the tumbling action is achieved.
Shear mixing will occur as a velocity gradient is produced, the top
layer moving with the greatest velocity and the velocity decreasing as
the distance from the surface increases.
When the bed tumbles, it dilates, allowing particles to move
downwards under gravity, diffusive mixing occurs.
Tumbler mixers
Too high a rotation speed will cause the material to be held on
the mixer walls by centrifugal force and too low a speed will
generate insufficient bed expansion and little shear mixing.
Tumbling mixers are available to mix from approximately 50 g,
e.g. for laboratory-scale development work, to over 100 kg at a
production scale.
The material typically occupies about a half to two thirds of the
mixer volume.
Addition of baffles or rotating bars will also cause convective
mixing (e.g. the V-mixer with agitator bar or blade).
Tumbler mixers
Applications
Tumbling mixers without agitator bar are good for free-flowing
powders/granules.
Unsuitable for cohesive/poorly flowing powders, because the shear
forces generated are usually insufficient to break up any aggregates.
Care must also be taken if there are significant differences in particle
size present, as segregation is likely to occur.
They mix powders with minimal energy imparted to powder bed:
→ they cause minimal size reduction (suitable for material that tend
to fracture).
Tumbler mixers
In pharmaceutical products manufacturing, it is often
preferable to use one piece of equipment to carry out more
than one function.
An example of this is the use of a mixer-granulator. As the
name suggests, it can both mix and granulate a product.
High-speed mixer granulator
The centrally mounted impeller blade at the bottom of the mixer rotates
at high speed, throwing the material towards the mixer bowl wall by
centrifugal force.
The material is then forced upwards before dropping back down
towards the centre of the mixer.
The particulate movement within the bowl tends to mix the components
quickly owing to high shear forces1 (arising from the high velocity) and
the expansion in bed volume that allows diffusive mixing2.
High-speed mixer granulator
Once mixed, granulating agent can be added and granules
formed in situ.
Applications:
Because of the high-speed movement within a mixer-
granulator, care must be taken if material fractures easily (i.e.
there might be unwanted particle size reduction).
This type of mixer is not normally used for blending lubricants
(due to risk of fracture for the particles).
High-speed mixer granulator
This type of mixer depends on the motion of a blade or paddle
through the product, and hence the main mixing mechanism
is convection.
Examples include:
the ribbon mixer.
the planetary mixer.
the Nautamixer.
Agitator mixers
Ribbon mixer
Mixing is achieved by the rotation of helical blades in a
hemispherical trough.
The ribbon mixer is top-loading, with bottom discharge port.
Agitator mixers
Ribbon mixer
It has a major disadvantage: the possibility of dead spots (areas
that remain unmixed) at the ends and in the corners of the
mixer.
Moreover the shearing action caused by the movement of the
blades may be insufficient to break up drug aggregates
(unsuitable for cohesive powders).
Applications:
Suitable for poorly flowing materials.
It is less likely to cause segregation than a tumbling mixer.
Agitator mixers
Nautamixer
The Nautamixer consists of a conical vessel
fitted at the base with a rotating screw, which
is fastened to the end of a rotating arm at the
upper end.
The screw conveys the material to near the
top, where it cascades back into the mass.
The mixer thus combines convective mixing1
(as the material is raised by the helical
conveyor) and shear2 and diffusive mixing3
(as the material cascades downwards)
Agitator mixers
Planetary mixer
Similar designs are used for both powder
and semi-solid mixing.
The bowl is raised up to the mixing blade for
the mixing process.
The mixing blade is carried on a rotating
arm.
It therefore travels round the circumference
of the mixing bowl, while simultaneously
rotating around its own axis.
Agitator mixers
This is therefore a double rotation
similar to that of a spinning plant
planet around the sun. From this the
name “Planetary mixer”.
Agitator mixers
Planetary mixer
Testing for blend homogeneity
This is usually done when one is developing a new formula and
procedure for a product and during scale up.
This is particularly true in case of expecting mixing problems
such as potent drugs.
Three issues must be considered:
A. Sample size: try to make your sample size equal to unit size.
For example if you testing a formula to be compressed to
tablets of 800 mg, then sample size of approximately 800 mg is
a good choice.
Testing for blend homogeneity
B. Number of samples: the larger the number of samples
taken from different locations, the more representative is the
sampling. One way to take samples is to view the powder
bed as three layers (top, middle and bottom) and each layer
is divided to into three locations: right, center and left. Taking
samples from the 9 locations is a reasonable way.
C. Sampling devices: There are two common sampling
devices
Testing for blend homogeneity
There are two common sampling devices:
A. Scoop: It has disadvantages:
Scooping cannot remove a sample from the middle or bottom of a
blender without considerable disturbance of the mixture.
Scooping from the top of powder may produce samples that were
segregated on standing.
B. Thief sampler: This is the most common device, which permits you to
take samples deep within the mixture without considerable
disturbance. It consists of outer and inner tubes.
Testing for blend homogeneity
The outer tube is pointed with openings at the bottom, middle
and top. The inner tube has dies or sample containers at the
same location of the openings of the outer tube. It also has a
handle to rotate inside the inner tube.
Testing for blend homogeneity
Before the insertion into the powder bed for sampling, the inner tube is
aligned so that the openings and dies do not match; thus upon insertion
no powder will be filled into the dies. After insertion, the inner tube is
rotated so the openings and dies match and the product flows in and
fills the dies. Then, openings and dies are re-unmatched and the whole
device is removed from the mix.
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