Mixed is not the same as staying mixed
The goal of blending is a uniform distribution: every scoopful, and ultimately every tablet, carries the same fraction of drug. But a powder blend is not a liquid solution — its particles are free to move on their own, and given the chance they will sort themselves by size and density. This drifting-apart of a once-uniform mix is segregation, and it is the constant adversary of content uniformity.
How segregation happens
The root cause is almost always a difference in particle properties — chiefly size, and secondarily density and shape. When particles differ, motion lets them separate. The classic mechanisms are worth recognising by sight.
- Sifting (percolation): small particles trickle down through the gaps between large ones whenever the bed is disturbed — the most common mechanism in hoppers.
- Trajectory: as powder pours, larger or denser particles fly farther and land apart from the fines, building side-to-side composition differences in a pile.
- Fluidisation / elutriation: air rushing up through a flowing powder lifts the lightest fines to the top, leaving the coarse below — common when filling fast.
A wide particle size distribution is the soil in which all three mechanisms grow. The further apart the drug and diluent sit in size or density, the more eagerly they separate. Low-dose drugs are the most exposed: when a few milligrams of potent active must spread evenly through hundreds of milligrams of excipient, even slight segregation can push individual tablets outside the label claim.
Designing segregation out
Because segregation feeds on differences, the cure is to remove the differences. The most powerful fix is wet granulation: binding the drug and excipients together into larger, uniform granules so each granule carries a fixed dose and nothing is free to separate. Other levers help too.
- Match the sizes. Choose a diluent grade whose particle size sits close to the drug's, so neither sifts past the other.
- Make the drug adhere. Micronised drug can be made to coat coarse carrier particles (an ordered or interactive mix) so it travels with the carrier rather than alone.
- Reduce handling. Shorten transfers, avoid free-fall into hoppers, and don't over-mix — gentle, minimal movement gives segregation fewer chances.