Segregation is one of the most common — and most misunderstood — problems in dry powder blending. It often explains why a blend initially passes homogeneity testing, only to fail later during transfer, discharge, or downstream processing.
For pharmaceutical manufacturers, segregation can lead to:
– Out-of-spec results
– Batch rejections
– Costly investigations and CAPAs
– Increased audit scrutiny
Understanding why segregation occurs — and how to troubleshoot it — is critical to maintaining blend integrity and regulatory compliance
What Is Segregation?
Segregation occurs when blended powders separate after mixing due to differences in their physical properties. Even a perfectly homogeneous blend can segregate if the system design or process conditions are not well controlled.
Unlike poor mixing, segregation typically happens after blending:
– During discharge
– During transfer
– During storage
– During filling or packaging
Common Causes of Segregation in Dry Powder Blending
Segregation is driven by physical forces acting on particles with different characteristics.
Particle Size Differences
Larger particles tend to rise, while finer particles migrate downward (percolation segregation). This is especially problematic with:
– API and excipient blends
– Micronised actives
– Wide particle size distributions
Density Differences
Heavier particles separate from lighter ones under vibration, gravity, or flow. Even small density differences can cause issues during discharge or transfer.
Particle Shape
Free-flowing spherical particles behave very differently to fibrous or irregular particles, increasing the risk of separation during movement.
Electrostatic Charge
Electrostatic forces can cause particles to cling to vessel walls or each other, leading to uneven distribution — particularly in low-humidity environments.
Over-Mixing
Contrary to intuition, longer mixing times can worsen segregation by allowing particles to stratify based on size or density.
Where Segregation Most Commonly Occurs
Many manufacturers focus on the blender itself, but segregation often happens outside the blending step:
– During blender discharge
– While transferring powder into IBCs, drums, or hoppers
– During vibration from conveyors or lifts
– During intermediate storage
– During tablet press or capsule filler feeding
A troubleshooting approach must look at the entire process, not just the blender.
Troubleshooting Checklist: Reducing Segregation Risk
Review Blender Fill Level
– Ideal working volume is typically 50–70%
– Underfilling increases particle movement
– Overfilling reduces effective mixing
Evaluate Blender Geometry
Blender shape and movement directly influence segregation risk. Poor geometry can:
– Promote dead zones
– Encourage stratification
– Cause uneven discharge
A well-designed tumble blender promotes gentle, randomised particle motion.
Assess Discharge Method
Segregation often begins at discharge:
– Free-fall discharge increases separation
– High drop heights exaggerate size and density effects
Controlled discharge and matched container interfaces help preserve blend integrity.
Consider Internal Blending Aids
For difficult formulations, optional internal blending tools (such as intensifier bars or enhanced mixing devices) can:
– Reduce blend time
– Improve dispersion of low-dose APIs
– Minimise segregation tendencies
Review Powder Handling After Blending
Key questions to ask:
– How many transfers occur after blending?
– Is the powder being vibrated or aerated?
– Are containers being moved or stored for long periods?
Minimising post-blend handling is often one of the most effective segregation controls.
Examine Environmental Conditions
Humidity and temperature influence:
– Electrostatic charge
– Flow behaviour
– Particle adhesion
Environmental controls are particularly important for fine or cohesive powders.
Segregation vs Homogeneity Failures: An Important Distinction
It’s critical to differentiate between:
– Poor mixing — the blend was never uniform
– Segregation — the blend was uniform, then separated
Misdiagnosing segregation as a mixing issue often leads to:
– Longer blend times
– Incorrect equipment changes
– Persistent failures
A proper investigation should include sampling at multiple stages, not just at the blender.
Designing Out Segregation from the Start
The most effective way to control segregation is to address it during equipment and process selection, including:
– Correct blender size and geometry
– Suitable discharge and transfer design
– Appropriate container systems
– Validation-friendly, repeatable processes
This is where early consultation and a well-defined URS become critical.
How Terriva Supports Segregation Control
Terriva works closely with pharmaceutical manufacturers to:
– Diagnose segregation risks
– Select appropriate blender geometry and scale
– Design controlled discharge and transfer solutions
– Support validation, FAT, and process optimisation
Our Pharmatech powder blenders are engineered to deliver repeatable, compliant blending performance, helping reduce both homogeneity failures and segregation risk across the full process.
If your blend looks uniform in the blender but fails later in the process, segregation — not mixing — is often the root cause.
Understanding where and why segregation occurs is the first step toward solving it permanently.
