Powder mixing

PCU 301
MR T. MANYARARA
• Majority of the active ingredients and
adjuvants used for the manufacture of
pharmaceutical dosage forms constitutes are
found in the powder form.
• A large market exists for solid dosage forms
involving powder processing.
• Therefore handling and processing of
pharmaceutical powders is key.
• Mixing is defined as shuffling type unit
operation process involving both large and small
particle groups and even individual particles.
• Mixing is an energy consuming process which
produces a random distribution of particles.
• It is dependent on the probability that an event
happens in a given time and once the desired
mixing has been attained, it is essential that the
particles in the mix cease movement so that the
system may exist in a state of static equilibrium
without segregation.
• Some of the parameters affecting efficient
mixing are:
a) Particle parameters like particle size, particle
shape, size distribution, particle density,
cohesivity, hygroscopicity and hardness.
b) Type of mixer: Speed, time, batch volume and
movement.
c) Segregation tendency of individual
components based on density difference.
 DRY MIXING:
• Mixing of solid powders has gradually evolved
from being an empirical process to being a
meticulously controlled process.
• Much of the scientific understanding of mixing
process has emerged from the behaviour of
non-cohesive binary particulate systems.
• For mixing to occur the individual particles
must be redistributed repeatedly within the
bulk, either by tumbling, shearing, scooping,
kneading or impaction.
• When the powder particles are freely distributed
within the bulk, there will be formation of either
free flowing or non-free flowing (cohesive)
mixtures depending on the particle size.
• Particles of larger diameter tend to be free
flowing and particles of small diameter tend to
be cohesive due to inter particulate forces
associated with the individual particles.
• Homogeneity of powder mixes can be ensured
by powder flow analysers, UV/VIS and NIR
Spectroscopy.
 TYPES OF MIXTURES:
• a) Free flowing mixtures
• Free flowing powders have desirable features
like minimal need of lubricant and effective
contact with die cavity.
• They suffer from a serious drawback of
segregation of individual components in post
mixing processing.
• The particles can move smoothly and
independently in a particular direction due to
the interparticulate forces.
• The free flowing powders need to be handled
and stored in a proper manner by packing the
products in polythene bags and applying
vacuum, before sealing.
b) Cohesive mixtures

• The cohesive mixture exhibits “stick-slip”

characteristics and the components are not free
flowing, the individual particles are repeatedly
broken down and allowed to redistribute within
the system to ensure a satisfactorily mixed
product.
• scale of segregation is less, but the intensity of
segregation will be more due to the retaining of
structure by the small agglomerates throughout
the mixing process.
• Some of the parameters contributing to the
formation of cohesive mixtures are moisture,
electrostatic charges, Van der waals forces and
solid bridges between the particles.

c) Ordered mixtures
• If one of the constituents of the powder mix is
added to a fine, micronized form then on
mixing the larger particles may adsorb some
of these smaller particles to active sites on
their surface where they are held tenaciously.
• Ordered mixtures are formed by mechanical,
adhesion or coating forces such that the
ordered unit will be the smallest possible
sample of the mix and will be of near identical
compositions to all other ordered units in the
mix.
 Mechanisms of mixing
• Mixing involves the following steps -
• Convective movement of relatively large portions of the
bed (Macromixing)
• Shear failure, which reduces the scale of segregation
• Diffusive movement of individual particles (Micromixing)
• A quantitative theory was developed to describe
mechanism of mixing in particulate systems in which one
component is present only in a trace quantity.
• Theoretical expressions were derived to predict the role
of mixing of the drug moiety.
Particle distribution during powder mixing
 SEGREGATION OR DEMIXING:
• All powder mixture have variable tendency to
separate during the processing, which can result
in poor quality product.
• Reasons responsible for demixing are,
(i) difference in particle size of various constituents.
(ii) density differences of various constituents.
(iii) Drug excipient interaction.
(iv) degree of agglomeration.
• The three main mechanisms for segregation of
powders are:
• Percolation: In a packed bed of powder, gravity
causes small particles to move into the voids
between larger particles, due to relatively larger
differences in particle size.
• Vibration: Upon vibrating of a bed of powder,
smaller particles will gradually move under the
bigger ones and thus lead to a separation of the
differently sized particles.
• Transportation: During the transport of powders, the
particles will be constantly accelerated and decelerated,
due to differences in trajectories of particles with different
masses and/or sizes these particles will be separated during
transportation.
• Similar effects happen when such powders are poured on a
heap. The heavier particles will roll to the outside of the
heap while the smaller concentrate in the centre of the
powder heap.
• The shape of the particles also plays an important role
during this type of segregation process.
• Special precautions must be taken during handling of these
powders by reducing the transportation velocity or the
falling height segregation is minimized.
 EVALUATION OF POWDER MIXTURE:
• Mixing process is critically affected by a
multitude of parameters like mixing time,
mechanism of mixing, type of mixer and batch
size.
• Various methods have been developed to
quantify the quality of mixture.
 MIXING INDEX
• There is always some variation in the
composition of the samples drawn from a
random mixture and the standard deviation in
the composition of large number of such
samples can be determined, provided an
accurate assay method is available.
• A random mix gives samples with low
standard deviation as compared to mixture of
the same components that have not reached
the random state.
• This phenomenon is used to define mixing
index, which is expressed as,
• M=Sr/Sact
• Where, Sr is the Standard deviation of samples
drawn from a fully random mix, Sact is actual
Standard deviation determined on the
partially mixed system.
• SCALE OF SCRUTINY
• Danckwert established the concept of scale of
scrutiny which describes the minimum size of the
regions of segregation in a particular mixture
which would cause it to be regarded as
insufficiently mixed.
• A poor mixture will have large scale of segregation
and high intensity of segregation and vice versa.
• As the scale and intensity of the mixture is reduced
the mixture passes from a stage of being
unsatisfactory to satisfactory mixture.
• Studies have revealed that the surface energy
of the powder particles can be utilized to
ensure the powder mix uniformity.
• There is also change in surface energy with
respect to size reduction or milling which in
turn affects the uniformity of the powder mix.
• The quality assessment of the mixture is only
valid at that scale of scrutiny.
 MIXER SELECTION:
• An ideal mixer should be capable of producing complete
blend in reasonable time without damaging the product.
• Additionally it should be dust-tight, require low
maintenance and energy, can be discharged and cleaned
easily.
• All these properties cannot be found in a single mixer.
• However, a logical selection of a mixer can be done based
on -
• Powder characteristics of the constituents of the mixture
• Quality requirements of the product
• Process requirements and limitations.
• Additionally the following points need to be considered,
to ensure overall success of a mixing process -
i. Does the mixer have flexibility to cope with a variable
batch size?
ii. Can the mixing vessel can be transported between the
operations like loading, mixing, packaging?
iii. Does it have easy access for sampling?
iv. How well can the mixer separate the process materials?
v. Does the mixer require frequent cleaning? If so what are
the standards?
vi. What should be the nature of the mixing surface?
• The effectiveness of a mixer depends on the
powders to be mixed, the time of mixing,
number of rotations of the mixer and other
factors, which may be characterized by
complex mathematical relationship.
• The performance of the mixers can be
predicted by using different powders with the
general theory of powder mixing using
Powder mixing monitor (POMM).
Quality Control: powder sampling
• There are two types of sampling methods that
can be used namely Stratified sampling and
Nested sampling.
• Stratified sampling is the process of selecting
samples deliberately from various locations
within a lot or batch or from various phases of
a process.
• This type is especially targeted to mixing in
blender or in compression, which have a
higher risk of failure in content uniformity.
• Nested sampling is the process of selecting
samples from one particular location within
the system.
• To obtain a truly representative sample the
following golden rules must be emphasized.
1. A powder should be sampled when it is in
motion
2. The whole stream of powder should be
sampled for short increments of time, instead
of part of the stream being sampled for the
whole time.
• The powder mixture cannot be sampled from
moving stream because of :
- the configuration of the mixer
- Size of the batch
- Possibility of mixture segregation biasing the
sample.
• So one is left with two options.
- scoop sampling of the bulk mixture.
- thief probing of the bulk mixture.
• Thief probing is preferred because the samples can be
taken from deep within the powder bed and a
reasonable degree of random sampling is achieved.
• Even a small diameter Thief probe is available which
eliminates the process of segregation.
• A four-thief probe design was found out for effective
sampling.
• Thief sampling is not always predictive of the
uniformity of the drug content of the finished dosage
forms.
• Therefore blending validation has become mandatory
partly through GMP and through court action (The
Barr decision).
• The root causes of blend or product content
uniformity problems are,
1) Non-optimum blending.
2) Thief sampling error.
3) Segregation
4) Weight control
5) Loss of component
6) Analytical error
7) Insufficient particle distribution.
• Sequential steps have to be followed to
troubleshoot such problems.
• A new statistical approach was proposed to
evaluate blend-sampling errors and a
systematic method is established for in
process blend test.
• Blend sampling errors plays an important role
in formulation of dosage form where blend
homogeneity is a must.