Introduction

During certain pharmaceutical operations, such as encapsulation

and tableting, problems arise due to the handling, transport, and
storage of powders. Considerable effort is often expended to blend
or mix several different species of powders (of various sizes,
shapes and densities), only to have the mixture de-mix or
segregate when transported. A well-mixed system may segregate
during transport to the tablet press and this may lead to pills that
do not fall within specifications. At present there is a lack of
understanding of the relationship between the collective motion of
the particles, and the particle properties, boundary conditions and
the history of the system.
Segregation
Segregation of powder and granular mixtures is a costly problem in the pharmaceutical industry. Most
manufactured products are mixtures of several components. Often the ingredients in a mixture
separate (segregate) during processing, resulting in an inconsistent final product.
❑ Segregation results when particles separate due to differences in their size, shape, or density.

❑ Segregation can result upon handling of a powder blend or material with varied particle size.

Powders that are not free flowing or that exhibit high forces of cohesion or adhesion between
particles of similar or dissimilar composition are often difficult to mix owing to agglomeration. The
clumps of particles can be broken down in such cases by the use of mixtures that generate high shear
forces or that subject the powder to impact. When these powders have been mixed, however, they
are less susceptible to segregation because of the relatively high interparticulates forces that resist
interparticulate motion, leading to unmixing.
Why is Segregation a Problem?
Segregation or poor blending can have many implications, including:
❑ Rejected product
❑ Variable color, look, or taste
❑ Excessive blend times
❑ Customer complaints
❑ Erratic dosage weight, mass
❑ Product or process delays
❑ Inconsistent particle size
❑ Poor quality control
❑ Validation failure
Importance of Powder Segregation in Pharma Manufacturing Processes
1. Mixing:
▪ Homogeneity: Proper mixing ensures a uniform distribution of active pharmaceutical ingredients (APIs)
and excipients, crucial for consistent dosage and efficacy.
▪ Segregation Risks: Segregation during or after mixing can lead to content uniformity issues, impacting
drug performance.
2. Compression:
▪ Tablet Uniformity: Segregation can cause variations in tablet weight and API content, affecting content
uniformity, potency and safety.
▪ Compression Issues: Non-uniform mixtures can lead to poor flow, affecting tablet hardness and
disintegration.
3. Encapsulation:
▪ Capsule Consistency: Uniform distribution of powder ensures each capsule contains the correct dose.
▪ Filling Accuracy: Segregation can cause weight variations and content uniformity issues in capsules.
4. Dry Powder Filling:
▪ Dosage Accuracy: Uniformity is critical for accurate dosing in dry powder inhalers and other devices.
▪ Flowability: Segregated powders may flow inconsistently, leading to dosing errors and production
inefficiencies.

Effective management of powder segregation is essential to maintain product quality, efficacy, and compliance
with regulatory standards in pharmaceutical manufacturing.
 How Segregation Can Occur?
▪ Segregation occurs when particles separate due to differences in
their size, shape, or density. It can be caused by the way in
which a powder blend is handled throughout the production
process.
▪ If dry granulation using roll compaction is a process step in your
pharmaceutical manufacture, again it is important to prevent
material from segregating as the quality of the granules produced
are dependent upon the quality of the in-feed from the IBC.

▪ It is well known in the industry that butterfly valve and slide

valve IBCs can cause material segregation as they create core
or funnel-flow during the discharge process. Flow of material
only occurs in a narrow vertical channel from the open area of the
outlet to the top surface of the material in the container, creating a
hole within the vessel, also known as ‘rat-holing’. As the material
on the top always prefers to flow towards the central core it results
in material being held along the sides of the vessel, as the powder
moves to the central core it enables particles to roll and separate
creating segregation.
Segregation Potential During Vacuum Conveying of Powders

1.Particle Size and Density: Differences in particle size and density can cause segregation as the powder
is conveyed.
2.Air Flow Rates: Variations in air velocity can lead to differential settling of particles.
3.Bends and Turns in Conveying System: Particles may separate at bends or turns due to changes in
velocity and direction.
4.Pipeline Length: Longer pipelines may result in more significant segregation due to prolonged exposure
to conveying forces.
5.Initial Homogeneity: The initial uniformity of the powder mixture influences segregation potential during
conveying.

Mitigating Segregation During Vacuum Conveying

1.Uniform Particle Size Distribution: Ensuring a narrow particle size distribution minimizes segregation.
2.Controlled Air Flow: Maintaining consistent air flow rates reduces differential particle movement.
3.System Design: Designing conveying systems with minimal bends and turns helps maintain uniform
particle distribution.
4.Blending: Incorporating blending steps before and after conveying to ensure homogeneity.
5.Material Choice: Selecting materials with similar densities and flow characteristics reduces segregation
tendencies.
Addressing these factors can help maintain the homogeneity of powder mixtures during vacuum conveying
processes in pharmaceutical manufacturing.
Factors influencing powder segregation

Segregation of powders can arise due to differences in physical and mechanical properties of
the constituent particles. The physical properties that are known to induce segregation are:

▪ size,
▪ shape,
▪ density,
▪ cohesivity,
▪ friction,
▪ surface texture,
▪ modulus of elasticity and
▪ coefficient of restitution.

The mechanisms of segregation are associated with different process conditions, such as,
vibration, fluidization, pouring in a heap, fall height, rate of feed, moisture and mixing
ratio. The main mechanisms of segregation are: displacement, sieving, percolation, sifting,
rolling, angle of repose, trajectory, impact, air current, fluidization and push-away effects.
 Segregation of powders during manufacturing of tablet
following direct compression method
Direct compression is the preferred method for the preparation of tablets due to its
simplicity compared to wet granulation and dry granulation. However, direct compression
blends are more prone to segregation, which can cause the undesirable separation of
active pharmaceutical ingredients (API) from excipients leading to variable potency of the
final drug product. Fluidization and sifting are the most common segregation
mechanisms encountered during direct compression blend handling. The fluidization
mechanism describes the vertical separation of particles induced by turbulent airflow,
which is experienced during freefall of materials. The sifting mechanism describes the
lateral separation of powders which can occur in funnel flow from hoppers. Therefore, the
direct compression blends exhibiting high segregation potential needs to be handled
appropriately to minimize content uniformity issues in the compressed tablets.
Factors affecting powder blend segregation during
encapsulation

Three factors might contribute to powder blend segregation during encapsulation and these are

▪ tapping length,
▪ tapping frequency and
▪ tapping acceleration.
Tapping motion is different from vibration motion as it has the tendency to induce percolation
type of segregation and not trajectory and vibro fluidisation type of segregation, the latter two
usually being induced by vibration motion. Therefore, tapping motion alone might induce less
segregation than vibration motion would. With tapping motion the powder bed becomes more
and more dense as the tapping continues and this is especially true for the lower part of powder
bed which, in turn, prevents the percolation type of segregation to occur.
Factors affecting powder blend segregation during
encapsulation(cont’d)
Prevention of the percolation type of segregation occurs because the drug particles
have difficulty percolating the dense bed. The above statements indicate that the
tapping length will not contribute much to segregation because it will help to form a
denser powder bed. The denser powder bed, as previously noted, prevents drug
particle percolation to the lower part of bed. As far as tapping frequency is concerned,
Staniforth’s studies indicated that vibration frequency between 20 and1,000 Hz did not
segregate powder blends of potassium chloride and crystallite lactose. Staniforth
concluded that proper selection of drugs/excipients combination is important to
minimize segregation. Tapping acceleration or intensity may induce fluidization or
percolation type of segregation.
Types of Powder Segregation
1.Percolation Segregation: Smaller particles move downward through voids between larger particles.
2.Trajectory Segregation: Particles segregate based on differences in size and density during free fall.
3.Elutriation Segregation: Lighter particles are carried upward by air currents while heavier particles
settle.
4.Vibration-Induced Segregation: Particles separate due to vibrations causing smaller particles to move
downward.

Factors Affecting Segregation

1.Particle Size: Differences in particle size can cause smaller particles to percolate through voids
between larger ones.
2.Particle Shape: Irregularly shaped particles can interlock and segregate differently compared to
spherical particles.
3.Particle Density: Heavier particles tend to settle more quickly than lighter particles.
4.Environmental Factors: Humidity and air currents can influence particle movement and segregation.
5.Processing Conditions: Vibration, mixing speed, and handling methods impact segregation
tendencies.
Addressing these factors is crucial for maintaining uniformity in solid dosage forms.
Types of segregation
Percolation segregation
– The movement of particles through the voids in the powder bed.
– It will occur in a static bed if the percolating particles are so small that they can fall into the
void spaces between the larger particles.
– The percolation also takes place for a short distance on either side of shear planes formed
during the mixing process and for this to occur there need be very little difference in particle
diameters. This is because of dilatation along the planes which separate the particles sufficiently
for smaller particles to move downwards.

Trajectory segregation
– During mixing particles are set in motion and kinetic energy is imparted to them.
– Larger particles have larger energies and tend to move a greater distance into the powder
mass before they are brought to rest. This may result in preferential separation and it can occur
in horizontal as well as vertical planes.
– Segregation by rolling: during pouring, a powder pile is formed and gradually built up. During
this pile formation, the larger particles, because of their mass, have tendency to roll down
outside the powder pile. On the other hand, fine particles have tendency to stick to the top and
concentrate in the middle of the pile.
Segregation
mechanisms
Common segregation
mechanisms include:
Sifting,
Fluidization, and
Dusting
Mechanisms of Powder Segregation

1.Sifting (Percolation): Smaller particles move downward through

voids between larger particles, often due to vibration or gravity.

2.Fluidization (Elutriation): Lighter or smaller particles are carried

upward by air currents, while heavier particles settle.

3.Trajectories (Throwing): Particles of different sizes and densities

separate when thrown through the air, as they follow different paths.

4.Rolling: Larger, rounder particles tend to roll to the sides or top of a

pile, while smaller, irregular particles remain in place.

5.Dusting: Fine particles become airborne and settle separately from

larger particles.
When & Where can Segregation
Occur?
Segregation often results during filling of a container, silo, or
hopper. It can also be caused by vibration, agitation, or other
unique forces acting on particles.
With sifting segregation, the fine particles concentrate under
the point of pile impact, while the coarse particles roll off to the
pile periphery.
With fluidization segregation, the fine particles in an aerated
powder locate towards the top of a container, while the coarse
particles deaerate quickly and settle to the bottom.
With dusting segregation, the ultra-fine powder component
settles at the silo or hopper walls.
The effects of segregation are strongly influenced by the type
of discharge pattern occurring in a silo, bin, or hopper.
Densification segregation

– Segregation due to density differences between particles may cause segregation if the mass
is subject to vibration.

– This can occur, for instance, in the hopper of a tablet machine and it is actively promoted
in vibratory sieving so as to place smaller particles directly over the mesh.

Dusting segregation

– Segregation may occur on discharge of a mixed powder for handling elsewhere. In recent
years equipment which can perform both mixing and other operations in the same vessel has
become popular. This avoids handling the mass between operations.
Blending (or mixing)
Blending (or mixing) is the opposite behavior of segregation. The process of blending
occurs when a collection of particles is homogenized or multiple ingredients are mixed
to obtain a uniform product. Some materials require gentle tumble blending in a
controlled batch mode while others require high shear to continuously blend highly
cohesive and tough-to-mix ingredients.

A well-blended material does not guarantee production of a quality

product due to segregation effects that may result during powder
flow.
Figure: In mass flow (A) In funnel flow Expanded flow
all material moves in the (B) the material (C) is a combination of mass
bin including near the moves in a central flow in the hopper exit and
walls. core with stagnant funnel flow in the bin above the
material near the hopper (normally used in retrofit
walls. situations).
In mass flow, the entire solids bed is in
motion when the material is discharged
from the outlet. Funnel flow occurs when
the walls of the hopper are not steep
enough or have low enough friction to
allow flow along them.
FUNNEL AND MASS FLOW PATTERNS ARCHING PROBLEM RATHOLING PROBLEM

Funnel flow is a non-uniform flow and is often referred to as a phenomenon called “rat holing,” whereby
material adheres to the walls of the hopper, resulting in challenges in content uniformity of the API in
the blend due to erratic and inconsistent flow pattern.
Segregation and cohesiveness

The tendency for blends to segregate is lower for more cohesive powders. The cohesiveness of
the powder can be achieved by

(1) micronization of the mixture,

(2) using poorly flowing excipient and

(3) affixing the drug particles to the excipients in the granules

It has been observed that there was little or no powder blend segregation during the handling
and encapsulating process if the following strategies are taken :
(1) proper selection of the formulation excipients,
(2) proper selection of the blend manufacturing processes, and
(3) the use of low tapping intensity.
Low tapping intensity can be achieved by selecting dispensing heads with more sieve holes or
same number of sieve holes but with larger diameters.
Preventing Segregation
The key to solving or preventing segregation is to evaluate the segregation tendencies of the
material and understand how the bulk material will transfer through your process in bins,
hoppers, chutes, or conveying systems. Mass flow discharge will reduce or eliminate the
effects of sifting and dusting segregation, while funnel flow will often worsen the effects.
Production people should have sufficient capabilities to diagnose the intricate differences
between a blending, sampling, and segregation problem.
 Solution of segregation problems

1) Selection of particular size fractions to 8) Use of multi-operation equipments to minimize

get drug and excipients of the same transfer of mix, e.g. a fluidized-bed drier or a high speed
narrow particle size range. mixer or granulator for mixing and granulating.
2) Milling/size reduction of components to
reduce the particle size range followed by 9) Mixing by serial dilution method or ordered mixing.
sieving to remove fines or lumps.
3) Controlled crystallization during 10) Selection of correct equipment e.g., use of nauta
production of the drug/excipients to give mixer or ribbon blender rather than tumbling mixer.
components of particular crystal shape or Traditional mass-flow bin can be replaced with
size range. mass-flow insert inside an existing bin in which insert
4) Selection of excipients with density consists of a hopper with in a hopper to provide uniform
similar to the active component (s). velocity profile in the bin that will minimize segregation.
5) Granulation of the powder mix for even
distribution of large number of different 11) Avoiding slopping surfaces in machinery.
particles in each granule.
6) Reduction of vibration or movement of 12) Minimizing transfer steps, drop height, and
powder mass after mixing. controlling fluidization of powder.
7) Use of filling machine hoppers
designed so that powder residence time is
minimized.
Dust clouds formation during material handling
 Prevention of dust clouds
In the production of drugs in solid dosage form (i.e., tablet capsules)
dusting and the resulting segregation can cause unacceptably high
variations in the concentration of active ingredient (which is usually only a
small percentage of blend). This poor content uniformity creates product
losses and safety hazards that can cost pharmaceutical manufacturers
millions of dollars annually. Transferring mixed powders from a blender to a
bin creates a dust cloud, which settles on top of the pile and concentrates
along the bin walls. This finer material, commonly the active ingredient,
often discharges at the end of a batch run, producing tablets that are not
within specifications. Entire batches are failed as a result.

The PharmaSok filling system is a new method of preventing these

problematic dust clouds from forming. It includes a rolling stand, FDA
compliant tubing (the “sock”), and a PLC -operated retraction unit.
The system is rolled in place beneath the blender, to which it is sealed. An
empty portable container is then positioned below the system. The operator
discharges the powder mixture from the blender through the PharmaSok,
into the container. Because the powder is completely contained, there is no
free-fall, and therefore, no dust cloud. The PharmaSok automatically
Fig.: PharmaSok filling system
retracts the tubing at a preset speed, filling the container gradually without
dust or segregation. The used tubing is automatically rolled up for easy
disposal as it retracts.
Cone Valve IBC Operational Steps
Cone Valve IBC
Key Benefits of Cone Valve Technology

▪ Guaranteed and controlled powder flow

▪ Prevent segregation of mixed materials
▪ Dust-free transfer of materials
▪ Accurate, automated discharge procedure
▪ Complete discharge for high yields
▪ Contained solution for product integrity
Pneumatic Slide Gate Valve Pneumatic Actuated Slide Gate Valve
 Case study
A batch of 100 kg powders blend for a tablet each containing 5mg API were kept in doubly
rapped poly bag in a plastic drum for one month in a in-process store room due to the shortage
of primary packaging materials. After receiving packaging materials, the powders blend were
carried to the compression machine manually by rolling the plastic drum. During compression of
the powder blend it was observed that both the main upper roller of the tablet machine were
having serious wear and tear, which was reflected by intermittent audible sound from the
machine. On routine analysis of the tablet by IPQC section, the tablets were having inconsistent
weights, less hardness and the content uniformity test did not comply with the specification.

a. Find out the specific root causes of the above problems

b. Mention the consiquences, if the above tablets were released for human consumption
c. How would you avoid these problems.