Blending Flashcards
Theory of mixing
1) Positive mix
- Complete & spontaneous mixing due to diffusion
- E.g. Miscible liquids
2) Negative mix
- Phases will separate unless work is carried out
- E.g. Suspensions (will sediment), immiscible liquids (e.g. oil & water)
3) Neutral mix
- Work required to mix
- Will NOT demix spontaneously
- E.g. Mixture of powders
Evaluation of mix
Mixed powders will always exhibit some variation in composition of powder
Target: Random mix
- Low standard deviation
Mixing mechanism
1) Convective
- Movement of a group of adjacent particles from one location to another within mixture
- E.g. Inserting spatula into powder bed and lifting a portion to be deposited elsewhere
2) Shear
- Slip planes formed as unstable fractions collapse
- Mixing occurs along interfaces of shear/slip planes
3) Diffusive
- Occurs when a body of powder is lifted beyond its angle of repose and starts avalanching –> particles tumble over each other (micromixing)
- Differences in the velocity of powder layers can help to migrate particles from one layer to another
- Redistribution of individual particles by the random movement of the particles relative to each other
Segregation often occurs during ___
Powder transfer
Segregation occurs due to differences in
1) Particle size
2) Particle shape
3) Density
Segregation results in
Loss of content uniformity
Segregation mechanisms
1) Percolation segregation
2) Elutriation segregation
3) Projection segregation
4) Feed/Heap segregation
5) Shear segregation
Percolation segregation
Occurs when powder bed is subjected to vibration / movement
- E.g. Expansion of particle bed, particle movement (usually occurs during powder transfer)
Finer / denser particles will percolate to the bottom
Typically seen in:
1) Bin that vibrates
Elutriation segregation
Occurs when their is air stream rushing through powder bed –> sifts out lighter/finer particles (will follow direction of air stream)
Typically seen in:
1) Filling empty tube with powder
- Displaced air during filling –> push finer particles up
Projection segregation
Occurs when a powder bed is projected into the air –> heavier particles will be projected further due to larger inertial forces
Typically seen in:
1) Under the outlet of a horizontal belt conveyer
Feed/Heap segregation
Larger/Heavier particles will roll down heap of powder
Typically seen:
1) Charging bin/hopper
Can be overcome by:
1) Having larger opening to allow mass flow of powder
Shear segregation
Occurs when 2 planes in a powder bed shear –> Finer particles of the top layer will fill the voids of the bottom layer
Typically seen when:
1) Powder flow down a slope
Ordered mixing - What is it
Finer particles mixed with larger/coarser carrier particles
Finer particles coat carrier particles
Constituent particles are not independent of each other
Ordered mixing - Application
Used for inhalation products
Ordered mixing - Segregation mechanisms
1) Ordered unit segregation
- Difference in size of carrier particles –> segregation of carrier particles
- Larger carrier particles will have more of the adsorbed component (i.e. more drug-rich)
2) Displacement segregation
- Addition of another component which may compete for carrier particle –> displaces adsorbed component
3) Saturation segregation
- Saturation of active sites on carrier particles
- Additional fine particles segregate via percolation
Geometric dilution
1) Take drug (small amount) & equivalent amount of excipient & blend
2) Take mixture & equivalent amount of excipient & blend
3) Repeat until all the excipient is used up
Shaped bin blenders - Types
1) V-cone, Y-cone
2) Double cone
Shaped bin blenders - Limitations
1) Tremendous shear involved when blending large amounts of powder
2) Large space/room needed to keep blender
3) Transfer of powder tends to be cumbersome, especially for large amounts
Shaped bin blenders - Applications
1) Mainly for small scale use
2) Largely replaced by IBC blenders in pharmaceutical production
Types of industrial blenders
1) High shear mixer
2) Paddle / Screw / Agitator mixer
3) Mechanofusion
Common laboratory blenders
1) Drum/Barrel hoop blender
- Container is rotated along axis that is least symmetrical
- Uses roller that will roll container in circular path
- Efficient & flexible mixing chamber change
2) Turbula mixer
- 3D movement –> very effective mixing
- Most common laboratory blender
- Popular in pharmaceutical / R&D
- Best used for free-flowing particles
Mixing process
Solid-solid mixing involves:
1) Expansion of powder bed
2) Application of 3D shear forces (e.g. rotation, vibration) to powder bed
3) Allow sufficient time to achieve random mix
4) Maintain random state
- Ensure no segregation occurs before ending mixing process
Factors affecting mixing
1) % actives
- Decrease in % actives (especially < 1%) –> difficult to mix small component with large component –> mixing more difficult
- Overcome by:
• Reduce particle size –> increase no. of particles
• Dissolve/Disperse in liquid medium –> spray coat larger particle
2) Particle size
- Smaller particle size –> increase no. of particles per unit weight –> better mixing
- BUT Smaller particles tend to agglomerate (especially particles in micron range)
3) Particle size distribution
- Narrow size distribution –> less densely packed (more void space) –> better mixing BUT more prone to segregation, especially when other ingredients are incorporated
- Broad size distribution –> more densely packed –> poorer mixing (may clump up) BUT less prone to segregation
4) Particle shape
- Rounder particles easier to mix BUT more prone to segregation
Test for blend homogeneity - Importance
Determine optimal mixing time
Test for blend homogeneity - When to carry out
1) Development
2) Scale-up
3) Change blender
Test for blend homogeneity - Important factors
1) Sample size
- Should be equivalent to unit dose
2) No. of samples
- Must be representative
3) Sampling device used
Test for blend homogeneity - Sampling devices
1) Spoon
- Not precise
- Generally avoid (but may be used in labs / small scale)
2) Thief key
- Can be inaccurate
- Only takes sample from one point
3) Core/Slot sampler
- Able to take samples from 3-5 points
- Can sample along blend axis
- Improves accuracy
- Commonly used
Test for blend homogeneity - Sample size
Should have sufficient sampling points
E.g. As many as 19 for 1000L IBC with thief key
Process variables in blending
1) Loading method
2) End point
3) Scale up
4) Material characteristics
Loading method
Loading methods:
1) Layering
- Split up each excipient and load one portion of largest excipient first, followed by other excipient(s) –> load active –> load largest excipient above active, followed by other excipient(s)
- Allows radial mixing (top-bottom mixing)
- More efficient –> reduces no. of revolutions to 10-20 revolutions
2) Side by side loading
- Requires side-by-side mixing
- Less efficient –> can take up to > 250 revolutions
Addition of lubricants
- Generally added at end of mixing process
- Overmixing –> cause waterproofing of drug (lubricants are generally hydrophobic)
End point determination - Key measure
No. of revolutions
Scaling up / Blending trials
Blending trials carried out to establish blending method
Carried out with:
1) Similar shaped bins
2) Smaller amounts of powder
- Volume of container in blending trials is 1/10 of volume of final container (1:10)
Material characteristics
Materials used (e.g. excipients, API) should be within reasonable specifications - For both blending trials & large scale mixing
Hygroscopic actives/agents can absorb moisture from excipients –> can cause dramatic change in blend characteristics –> discharge problems & or balling
Fill ratio / % Fill
Optimal: 60% (55 - 70%) (2/3 of container)
Too little fill
- A lot of air space –> segregation can occur
- Require greater no. of revolutions
Too much fill
- No/Little air space above powder –> no space for powder to rotate/roll around & mix
Current trends
1) Containment
- Contained additions in blending room (minimize transfer)
- Contained sampling
- Milling blending modules - Integrated standard units (reduce contact with product)
- Non-GMP production areas
- Through-the-wall installations
2) Process analytical technology (PAT)
- In-line monitoring e.g. NIR
Must ensure ___ during powder transfer
1) Good flow
2) No segregation
Overcoming powder flow issues
Vibration
1) External vibration
2) Internal vibration
External vibration
Frame vibration
IBC vibration
Internal vibration
E.g. Vibroflow
Limitations of vibration
1) Causes segregation
Choice of external VS internal vibrator depends on:
1) Compaction
2) Segregation
3) Noise
4) IBC damage
5) Weighing system
- External vibration may damage weighing scale
6) Dosing capability
7) Product residue
- Internal vibrator may cause some product to be retained in container
Key factors for bin: blending
1) Blend critical parameters
- No. of revolutions
- % fill
- Loading method
- Sampling method
- Formulation
2) Simple scale up process
3) Contained process
NIR - Benefits
1) No operator contact - safety
2) No sampling error - no thief
3) Real time information
4) Multi-ingredient uniformity
5) Process understanding
6) Process finger-printing for scale up
7) Right first time
8) Fast release of blend - reduced cycle times
NIR - Indicates good mixing when
Spectra are highly reproducible
