Motivation

High cost of process failures: wasted batches, delayed development, compromised

validation
Industrial powder blending is not fully understood. Design of blending equipment
is based on empirical methods
Tumbling blenders are the most common devices used to mix powders
Methods to predict and prevent segregation are available but rarely used
High shear mixers are widely used for cohesive powders, however little is known
about mixing and segregation in these devices
Rational criteria for comparing mixing performance in different types of equipment
are unavailable
Rigorous scale-up procedures remain to be developed
Scale up for powders is totally empirical.
There are a few equations but they dont work.
Challenges
The process is INTRINSICALLY TIME DEPENDENT
A single input (blender speed) can affect many outputs (shear rate, lubrication,
density, cohesion)
Problem is essentially multivariate correction of one undesirable effect can lead to
other forms of performance degradation.
Low melting point ingredients tend to smear on the surface of other ingredient.
The agglomeration of drug material could be a huge problem.
Technical factors to consider in blending
Main problems causing poor content uniformity: Weight variability, incomplete
mixing, segregation, agglomeration
Incomplete mixing is typically caused by poor process design (high fill level, short
mixing time) or poor loading practices
Segregation may be driven by different factors: particle size and density
differences, crystal shape, roughness, and cohesion However, most problems are
caused by particle size differences generated by the raw materials or the
granulation steps
Agglomeration is characteristic of cohesive systems and can sometimes be solved
by high-shear mixing; however, intensity and duration of shear steps are critical.
Powders can (and do) agglomerate in blenders
Role of shear in scale up/down is unclear
Performance of blenders depends on how you loaded the powder.
The number of revolutions also depends on how the blender is loaded.
Agglomeration can be a huge issue if the API content is low.
Agglomerate, in such case, can highly affect the potency of the tablet by atleast 3040%.
Tumbling blenders mix very fast in the direction of motion and very slow in the
orthogonal direction along the axis of rotation the mixing is very slow process

Tend to promote segregation. Particles follow a path and repeat a route and tend to
separate more and more. The other reason is that tumblers are used for free flowing
materialswith larger particle size which promotes segregation.
It is relatively easy to load or unload the powder.
Convective blenders are poorly characterized. Have a lot of dead spots. Are
difficult to empty
Conversely, they have a lower tendency towards segregation. They use blades tat
avoid repetition of motion. Also, they use more cohesive powders which tend to
segregate less.
Three main mechanisms for mixing (J.C. Williams)
Convection
Driven by bulk flow
Fast macromixing
Easy to scale up
Limited by segregated flow structures (incomplete mixing)
Dispersion
Driven by individual particle motion
Always slow
Leads to complete macroscopic homogeneity
Scale-up criteria unknown
Shear
Caused by velocity gradients
Required for micromixing of cohesive systems
Scale-up criteria unknown
The blenders that have one of the arms longer than the other are called Cross flow
V blenders. It is done to promote cross flow.
Intensifier bar can cause more agglomeration due to energy by friction.
The important unit of mixing is number of Revolutions and not RPM.
The RPM should be low enough such that inertia is not important.
If you allow the RPM to be so high that shear centrifugal acceleration exceeds about
25% of gravity, then inertia will become important.
Non cohesive (free flowing) powders do not require shear to mix.
In blender, never exceed 70% of the fill capacity.
Load the blender symmetrically. Make sure your initial pattern has same ingredients
on both sides.
Make sure the drug is loaded symmetrically.
Blend standard deviation v/s revolutions: Mixing Curve
Mixing in Double Cone
Strong convective motion
Slow axial dispersion
Mixing within axial slices is a combination of convective and dispersive transport
Mixing between axial slices is mainly dispersive and very slow
Breaking symmetry and disrupting powder flow would improve mixing

In double cone, if the materials are placed one above the other, mixing is very fast.
If they are placed side by side, the mixing is very slow.
If the V blender is tilted, we end up with large particles on the lower side.
Cohesion and electrostatics are the major factors to be considered during
segregation.