blending and blend assessments Flashcards
positive mix:
complete and spontaneous mix resulting from diffusion, no energy input needed
negative mix:
phases separate unless work is carried out
neutral mix:
work required to mix – when stopped does not demix spontaneously
causative factors of segregation
diff in particle size
diff in particle shape
diff in particle density
general mechanisms of segregation
- Percolation: Powder bed dilated due to agitation, causes finer/denser particles to percolate to the bottom
- Elutriation: Air stream through powder bed sift finer particles
- Projection: Heavier particles projected further in air
- Feed/heap: Heavier powder roll further down a heap of powder
- Shear: Two planes in powder bed, finer powder from top layer fills voids of bottom layer
Importance of blending in Pharmaceutical dosage forms
Achieve content uniformity of dosage form
What is blending/mixing
An operation to produce homogenous mixture where all component constituents are found to be well distributed and in close contact with each other
Describe the three mixing mechanisms
- Convective: Lift a portion of powder from bed and deposit somewhere else
- Shear: Form slip planes, slide over one another. Shear mixing occur at interfaces
- Diffusive: Particles avalanche when lifted beyond angle of repose, tumbling over each other. Aka micromixing as it involves individual particles (unlike shear and convective)
In what processes are different segregation commonly observed?
- Percolation: A vibrating bin
- Elutriation: Filling an empty tube with powder
- Projection: Outlet of horizontal belt conveyer
- Feed/heap: Charging a hopper/bin
- Shear: Powder blend flowing downslope
Purpose of geometric dilution
Mix a small amount of ingredient with a larger entity
Some examples of shaped bin blenders. What are their disadvantages which caused them to be replaced by IBC blenders?
V-cone, Y-cone, Double cone
Disadvantages:
- Require a lot of space
- Significant shear segregation when releasing powder
Commonly used pharmaceutical industrial mixers
- High Shear mixer
- IBC
Common Lab Blenders
- Drum/Barrel Hoop Blender
- Turbula Mixer: Provide 3D movement, leads to effective mixing (best for free-flowing powders)
Describe the solid-solid mixing process
- Expansion of solid bed
- Application of 3D shear forces to bed
- Allow time to achieve random mix
- Maintain random state
Most suitable sampling method to increase accuracy
Core sampling: Insert and takes 3-5 sample points along the way
Process variables in blending
- Loading method
- End-point determination: Using no. of rev
- Scale-up
- Material characteristics
Between top-bottom mixing and side-side mixing, which is better?
Top-bottom mixing
Process of mixing:
- Expansion of beds of solids: so that there is space for the particles to go between each other
- Application of 3D shear forces to powder bed
- Allow for sufficient time to achieve random mix
- Maintain random state
Factors affecting mixing:
% of actives: as % decreases, more difficult especially <1% – for best outcomes, use random mixing and decrease particle size
Particle size: if decreased, there is increased number/unit weight but can agglomerate
Particle size distribution: affects packing and bulk density and densely packed ones are more difficult to mix
Particle shape: affects flow and friction – spherical particles are easier to mix but easier to segregate as well
Aim of testing for blend homogenity:
Impt to determine optimal mixing time
usually carried out during development, scale-up phase/when changing blender
Purpose of Near Infra-Red Analysis in Powder Blending
Quantitative assessment of Homogeneity to determine end-point of blending (from SD against no. of rotations graph)
steps of sampling:
define sampling method
Need to find a consistent pattern to ensure results are comparable
need to have sufficient sampling points
Suitable available sampling devices
Scoop (avoid) Conventional thief keys can be inaccurate Core sampler (higher accuracy)
Process variables in blending:
Loading method endpoint determination material characteristics filling method -- rotation effects fill level for mixing
optimal fill level for mixing:
60%
%fill is a key process parameter. How does it affect the mixing?
Effects the number of complete revolutions required for complete mixing
What are two powder flow issues in blending, and the solutions to one of them?
Issues:
- No flow
- Segregation
For no flow:
- External (e.g. frame vibration, IBC vibration)
- Internal vibration (wire in IBC)
What are the key blending parameters?
- No. of revolutions
- %fill
- Loading methods
- Sampling methods
- Formulation
Purpose of Near Infra-Red Analysis in Powder Blending
Quantitative assessment of Homogeneity to determine end-point of blending
Powder flow issues in mixing:
no flow
segregation
if no flow, add:
External vibration: frame/IBC vibration
internal vibration: vibroflow (wire that vibrates inside the container and cause flow)
Key factors for blending bin:
1. blend critical parameters: number of revolutions % fill loading method sampling method formulation 2. simple scale up 3. contained process
What are some of the material characteristics that have to be taken note of when blending?
On storage, hygroscopic actives/agents can absorb moisture from excipients
- can cause dramatic changes to blend characteristics and discharge problems/balling
what type of rotation is more suitable for efficient blending?
top-bottom mixing due to more space for container expansion
Why is loading method important for blending?
layering decrease number of blend revolutions
layering of large volumes of excipients/actives will increase efficacy (lubricants no need and are added at the top)
Use of NIR in PAT manufacturing
no operator contact no sampling errors real time information multi-ingredient uniformity process understanding process finger printing for scale up right first time fast release of blend and reduce cycle times
Quantitative assessment of homogenity:
SD of absorbance at characteristic wavelength used to predict
homogenous mixture reached when SD against rotation time approaches min-value, showing that there is uniform distribution of the particles
Benefits of NIR for end point contact:
Non-invasive adopted as routine approach for real-time determination of blend homogenity
replace conventional method as less labourious, more sensitive, less intrusive, less biased
Replace use of rpm/process time to determine end point
