Chapter Eleven: Mixing


- no input energy required

Mixing Principles - do not present any problems during
Importance of Mixing
manufacture
- ensures an even distribution of the
active components
Negative Mixtures - components tend to
- an even appearance and
separate out
- dosage form releases the drug at
- energy must be quickly input to keep
correct site and at desired rate
components adequately dispersed
- also important in granulation, drying
- more difficult to form and to maintain
and coating - requires high degree of mixing
Products utilizing mixing
efficiency
• tablets, capsules, sachets and dry
ex. (slow separation) emulsions, creams,
powder
viscous suspensions
• inhalers - mixtures of solid particles
• linctuses - mixtures of miscible liquids
Neutral Mixtures - static in behaviour
• emulsions and creams - mixtures of - are capable of demixing
immiscible liquids - requires energy input
• pastes and suspensions - dispersions of
ex. powders, pastes, and ointments
solid particles

Type of mixtures CAN CHANGE

Definition and Objectives of Mixing
Mixing - a unit operation that aims to
treat two or more components, initially in
an unmixed or partially mixed state, so
that each unit of the components lies as
nearly as possible in contact with a unit
of each of the other components - thus
producing:
during processing
The Mixing Process
Powder mixing, is a 'chance' process
Perfect Mix - or a theoretical ideal. This is
no normally practicable, is actually
unnecessary, and undesirable

Perfect Mix - or a theoretical ideal. This is Random Mix - a mix where the
no normally practicable, is actually probability of selecting a particular type
unnecessary, and undesirable of particle is the same at all positions and
is equal to the proportion of such
Types of Mixtures particles in the total mix
Positive Mixtures - form gases or miscible
liquids which mix spontaneously and
irreversibly by diffusion
- tend to approach a perfect mix

ysdychinco'18
Scale of Scrutiny - weight or volume of • indicate when sufficient mixing has
the dosage unit which dictates how much occurred
closely the mix must be examined / • asses the efficiency of a mixer
analysed to ensure it contains the correct • determine the mixing time required for
dose / concentration a particular process
- the amount of material within which
the quality of mixing is important Mechanisms of Mixing and
Demixing
The number of particles contained in the
Powders - particles must move relative
scale of scrutiny depends on:
to each other
• sample weight
Main mechanisms by which powder
• particle size
mixing occurs:

• particle density
Convective Mixing - transfer of relatively
large groups of particles from one part of
2 Important Conclusions:
the powder bed to another
1. The lower the proportion of active
- contributes to the macroscopic mixing
component present in the mixture,
of powder mixtures and tends to
the more difficult it is to achieve an
produce a large degree of mixing fairly
acceptably low deviation in active
quickly
content
2. The more particles there are present
Shear Mixing - a 'layer' of material flows
in a unit dose / scale of scrutiny, the
over another 'layer' resulting in the layers
lower the likely deviation in content
moving at different speeds and therefore
mixing at the layer interface
• To decrease deviation, one must


increase the number of particles in the
Diffusion - movement of individual
unit dose by decreasing the particle
particles
size - however, may lead to particle
- the potential for powder particles to
agglomeration
pass through the void spaces created
either under gravitational forces or by
The aim during formulation and
force movement
processing is to minimize the variation
to acceptable levels by selecting an
Liquids -

appropriate scale of scrutiny, particle
Main mechanisms by which powder
size, and mixing procedure
mixing occurs:
Bulk Transport - analogous to the
Evaluation of the Degree of Mixing
convective mixing of powders
• indicate the degree / extent of mixing
• follow a mixing process

ysdychinco'18
Turbulent Mixing - arises from the
haphazard movement of molecules when
forced to move in a turbulent manner
- induced turbulence is a highly effective
mechanism for mixing
Eddies - small groups of molecules
moving together as a unit, reduce in size
and eventually break up, being replaced
by new eddies
Molecular Diffusion - analogous to
diffusive mixing in powders
- occurs with miscible fluids where a
concentration gradient exists
- produce a well-mixed product
Powder Segregation
(Demixing)
- very important because an already
formed random mix may change to a
non-random mix, or a random mix may
never be achieved
- will cause an increase in content
variation in samples taken from the mix
- arises because powder mixes are not
composed of monosized spherical
particles, instead differ in size, shape,
density and surface properties
Particle Size Effects
Percolation Segregation - smaller
particles tend to fall through the voids
between larger particles and thus move
to the bottom of the mass
Trajectory Segregation - larger particles
will tend to have greater kinetic energy
imparted to them, thus move greater
distances
ysdychinco'18
Elutharian Segregation - tendency of
"dust" to be blown upwards by turbulent
air currents - subsequently forming a
layer on top of the coarser particles
Particle Density Effects - more dense
particles will have a tendency to move
downwards regardless of particle size
Particle Shape Effects
• Spherical particles exhibit the greatest
flowability, hence are easily mixed.
However, segregate more easily than
non-spherical particles
• Irregular / needle-shaped particles may
become interlocked, decreasing
tendencies of segregation
During the initial stages of the process,
the rate of mixing > rate of demixing
After period of time, rate of demixing
may predominate until equilibrium
state is reached - random mix will be
impeded
Approaches to Minimize Segregation
• Selection of particular size fraction to
achieve same narrow particle size range
• Milling of components to reduce
particle size range or ensure particles
measure > 30 um
• Controlled crystallization during
production of the drug / excipients
• Selection of excipients which have a
density similar to the active component
• Granulation of the powder mix - to
ensure even distribution in each unit
• Reduce the extent to which the powder
mass is subjected to movement after
mixing
• Use filling machine hoppers
• Use equipment where several
operations may be done
• Production of an "ordered" mix (also
referred as adhesive or interactive
mixing)
Ordered Mixing - adsorption of powders
into onto 'active sites' on the surface of
larger 'carrier' particles and exhibit great
resistance to dislodging
- minimizes effect of segregation while
maintaining good flow properties
- important in direct-compression tablet
formulation
- also utilized by Dry powder inhaler
formulations
- particles may be dislodged due to
excessive vibration
Segregation in Ordered Mixes
• Ordered Unit Segregation - the carriers
vary in size
• Displacement Segregation -
competition on active sites of carrier
particles (magnesium stearate as
lubricant for tablet formation)
• Saturation Segregation - there are
insufficient carrier particles
Mixing of Powders

Powder-mixing Equipment
 Turbine mixers - is used for more viscous
Tumbling mixers / blenders - for free-
flowing powders 
 - will not cope with liquids of very high
(y-cone, drum mixers, double-cone, twin
shell, cube)
• addition of 'prongs' baffles or rotating
bars will also cause convective mixing
• material occupies half to two-thirds of
the mixer volume
ysdychinco'18
• less effective for cohesive / poorly
flowing powders
High-speed mixer-granulators - can do
both mixing and granulating
• not used for blending lubricants
Fluidized-bed mixers - main use is in the
drying of granules or the coating of
multiparticulates
• can be used to mix powders prior to
granulation
Agitator mixers - main mixing mechanism
is convection
1. Ribbon Mixer - rotation of helical
blades in a hemispherical trough.
'Dead spots' are difficult to eliminate
- can mix poorly flowing materials
and is less likely to cause
segregation
2. Planetary Mixer - used for both
powder and semi-sold mixing
Mixing of Miscible Liquids and
Suspensions

Mixers for Miscible Liquids and
Suspensions

Propeller mixers - common arrangement
for medium-scale fluid mixing
fluids
viscosity
- used for emulsions and creams
In-line mixers - makes continuous mixing
processes possible

Mixing of Semi-solids

Mixers for semi-solids
Planetary mixers - commonly found in
domestic kitchens
- 'scraping down' of bowl is necessary

Sigma Blade mixers - robust mixer deals

with stiff pastes and ointments

Further treatment of semisolid

dispersions - further action of a roller mill
or colloid mill so as to 'rub out' these
particles

ysdychinco'18