mixing Flashcards
What products need mixing
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.
What is the theoretical definition of mixing
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)
What’s the 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.
What is segregation
opposite effect to mixing, i.e. components
tend to separate out.
Segregation happens during or after mixing
Why does segregation happen
because powder mixes encountered
practically are not composed of mono-sized spherical particles,
but contain particles that differ in size1, shape2 and density3.
What are the factors that affect mixing
- Scale of scrutiny
- % of the active ingredient
- Particle size
- Particle size distribution
- Particle shape
- Particle density
- Mixing time
How does the scale of scrutiny affect mixing
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).
How does the % of the active affect mixing
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.
How does the particle size affect mixing
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.
How does particle size distribution affect mixing
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.
What is percolation segregation
Smaller particles tend to fall through the voids between larger
ones and so move to the bottom of the mass.
What is trajectory segregation
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
How does particle shape affect mixing
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.
How does particle density affect mixing
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
How does the mixing time affect mixing
- Non-segregating mixes will improve with continued increases in
mixing time. - 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.
How can we minimize segregation
- 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. - Selection of excipients which have a density similar to the active
component. - Selection of an optimum mixing time.
- Reducing the extent to which the powder mass is subjected to vibration or
movement after mixing
What are the mechanisms of mixing
- Convection.
- Shear.
- Diffusion.
What is 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.
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
What is the shear mechanism (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
What is the diffusion mechanism ( 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.
Shear and convective mixing can quickly produce a rough mix but
local groups of particles may remain unseparated unless subjected to
diffusive mixing.
What is ordered mixing
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
Give an example on 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
What are Tumbler mixers
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).
