mixing

Question 1

What products need mixing

Answer 1

 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.

Question 2

What is the theoretical definition of mixing

Answer 2

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
(results in a perfect mix)

Question 3

What’s the objective of mixing

Answer 3

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.

Question 4

What is segregation

Answer 4

opposite effect to mixing, i.e. components
tend to separate out.

 Segregation happens during or after mixing

Question 5

Why does segregation happen

Answer 5

because powder mixes encountered
practically are not composed of mono-sized spherical particles,
but contain particles that differ in size1, shape2 and density3.

Question 6

What are the factors that affect mixing

Answer 6

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

Question 7

How does the scale of scrutiny affect mixing

Answer 7

 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.

 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).

Question 8

How does the % of the active affect mixing

Answer 8

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.

Question 9

How does the particle size affect mixing

Answer 9

Reduction of particle size will increase the number of particles
per dosage unit and lead to improvement in achieving
homogenous mixing.

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.

Question 10

How does particle size distribution affect mixing

Answer 10

the narrower the particle size distribution the better the
flow and the easier the mixing.

Wide particle size distribution can lead to segregation during or after
mixing. Two most common types of segregation: percolation
segregation and trajectory segregation.

Question 11

What is percolation segregation

Answer 11

Smaller particles tend to fall through the voids between larger
ones and so move to the bottom of the mass.

Question 12

What is trajectory segregation

Answer 12

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

Question 13

How does particle shape affect mixing

Answer 13

 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.

Question 14

How does particle density affect mixing

Answer 14

 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

Question 15

How does the mixing time affect mixing

Answer 15

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.

Question 16

How can we minimize segregation

Answer 16

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

Question 17

What are the mechanisms of mixing

Answer 17

1. Convection.
2. Shear.
3. Diffusion.

Question 18

What is convection (macroscopic mixing)

Answer 18

 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.

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

Question 19

What is the shear mechanism (macroscopic mixing)

Answer 19

 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

Question 20

What is the diffusion mechanism ( microscopic mixing)

Answer 20

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.

Question 21

Shear and convective mixing can quickly produce a rough mix but
local groups of particles may remain unseparated unless subjected to
diffusive mixing.

Question 22

What is ordered mixing

Answer 22

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.

This has the effect of minimizing segregation while maintaining
good flow properties

Due to cohesive/adhesive forces

Good for potent mixes

Question 23

Give an example on ordered mixing

Answer 23

 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

Question 24

What are Tumbler mixers

Answer 24

Used for granules and free flowing powders

Many designs like cube and drum mixers

With or without agitator mixing blade

When operated at the correct speed, shear missing will happen along with diffusion mixing

High-speed — will hold to the walls due to centrifugal force

Low speed—– low bed expansion and mixing

Used for both laboratory and production scale mixing

Adding a bar will result in convection mixing

 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).

Question 25

What are high-speed mixer granulators

Answer 25

One piece equipment with multiple functions (mixing and granulation )

 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.

Shear and diffusion

Once mixed, granulating agent can be added and granules
formed in situ.
Applications:
Because of the high-speed movement within a mixergranulator, 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

Question 26

What are agitator mixers

Answer 26

the main mixing mechanism
is convection.
 Examples include:
 the ribbon mixer.
 the planetary mixer.
 the Nautamixer.

Question 27

How does the ribbon mixer work

Answer 27

For the 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.
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.

Question 28

How does the nautamixer work

Answer 28

 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)

Question 29

How does the planetary mixer work

Answer 29

 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
This is therefore a double rotation
similar to that of a spinning plant
planet around the sun. From this the
name “Planetary mixer”.

Question 30

When do we test for homogeneity

Answer 30

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.

Question 31

What should we consider while texting for homogeneity

Answer 31

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.

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

Question 32

What are the methods used in sampling

Answer 32

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.