blending and blend assessments

Question 1

positive mix:

Answer 1

complete and spontaneous mix resulting from diffusion, no energy input needed

Question 2

negative mix:

Answer 2

phases separate unless work is carried out

Question 3

neutral mix:

Answer 3

work required to mix – when stopped does not demix spontaneously

Question 4

causative factors of segregation

Answer 4

diff in particle size
diff in particle shape
diff in particle density

Question 5

general mechanisms of segregation

Answer 5

• 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

Question 6

Importance of blending in Pharmaceutical dosage forms

Answer 6

Achieve content uniformity of dosage form

Question 7

What is blending/mixing

Answer 7

An operation to produce homogenous mixture where all component constituents are found to be well distributed and in close contact with each other

Question 8

Describe the three mixing mechanisms

Answer 8

1. Convective: Lift a portion of powder from bed and deposit somewhere else
2. Shear: Form slip planes, slide over one another. Shear mixing occur at interfaces
3. Diffusive: Particles avalanche when lifted beyond angle of repose, tumbling over each other. Aka micromixing as it involves individual particles (unlike shear and convective)

Question 9

In what processes are different segregation commonly observed?

Answer 9

• 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

Question 10

Purpose of geometric dilution

Answer 10

Mix a small amount of ingredient with a larger entity

Question 11

Some examples of shaped bin blenders. What are their disadvantages which caused them to be replaced by IBC blenders?

Answer 11

V-cone, Y-cone, Double cone

Disadvantages:

• Require a lot of space
• Significant shear segregation when releasing powder

Question 12

Commonly used pharmaceutical industrial mixers

Answer 12

• High Shear mixer

- IBC

Question 13

Common Lab Blenders

Answer 13

• Drum/Barrel Hoop Blender

- Turbula Mixer: Provide 3D movement, leads to effective mixing (best for free-flowing powders)

Question 14

Describe the solid-solid mixing process

Answer 14

• Expansion of solid bed
• Application of 3D shear forces to bed
• Allow time to achieve random mix
• Maintain random state

Question 15

Most suitable sampling method to increase accuracy

Answer 15

Core sampling: Insert and takes 3-5 sample points along the way

Question 16

Process variables in blending

Answer 16

1. Loading method
2. End-point determination: Using no. of rev
3. Scale-up
4. Material characteristics

Question 17

Between top-bottom mixing and side-side mixing, which is better?

Answer 17

Top-bottom mixing

Question 18

Process of mixing:

Answer 18

1. Expansion of beds of solids: so that there is space for the particles to go between each other
2. Application of 3D shear forces to powder bed
3. Allow for sufficient time to achieve random mix
4. Maintain random state

Question 19

Factors affecting mixing:

Answer 19

% 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

Question 20

Aim of testing for blend homogenity:

Answer 20

Impt to determine optimal mixing time

usually carried out during development, scale-up phase/when changing blender

Question 21

Purpose of Near Infra-Red Analysis in Powder Blending

Answer 21

Quantitative assessment of Homogeneity to determine end-point of blending (from SD against no. of rotations graph)

Question 22

steps of sampling:

Answer 22

define sampling method
Need to find a consistent pattern to ensure results are comparable
need to have sufficient sampling points

Question 23

Suitable available sampling devices

Answer 23

Scoop (avoid) 
Conventional thief keys can be inaccurate 
Core sampler (higher accuracy)

Question 24

Process variables in blending:

Answer 24

Loading method 
endpoint determination 
material characteristics
filling method -- rotation effects 
fill level for mixing

Question 25

optimal fill level for mixing:

Answer 25

60%

Question 26

%fill is a key process parameter. How does it affect the mixing?

Answer 26

Effects the number of complete revolutions required for complete mixing

Question 27

What are two powder flow issues in blending, and the solutions to one of them?

Answer 27

Issues:

• No flow
• Segregation

For no flow:

• External (e.g. frame vibration, IBC vibration)
• Internal vibration (wire in IBC)

Question 28

What are the key blending parameters?

Answer 28

1. No. of revolutions
2. %fill
3. Loading methods
4. Sampling methods
5. Formulation

Question 29

Purpose of Near Infra-Red Analysis in Powder Blending

Answer 29

Quantitative assessment of Homogeneity to determine end-point of blending

Question 30

Powder flow issues in mixing:

Answer 30

no flow

segregation

Question 31

if no flow, add:

Answer 31

External vibration: frame/IBC vibration

internal vibration: vibroflow (wire that vibrates inside the container and cause flow)

Question 32

Key factors for blending bin:

Answer 32

1. blend critical parameters: 
number of revolutions 
% fill 
loading method 
sampling method 
formulation 
2. simple scale up 
3. contained process

Question 33

What are some of the material characteristics that have to be taken note of when blending?

Answer 33

On storage, hygroscopic actives/agents can absorb moisture from excipients
- can cause dramatic changes to blend characteristics and discharge problems/balling

Question 34

what type of rotation is more suitable for efficient blending?

Answer 34

top-bottom mixing due to more space for container expansion

Question 35

Why is loading method important for blending?

Answer 35

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)

Question 36

Use of NIR in PAT manufacturing

Answer 36

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

Question 37

Quantitative assessment of homogenity:

Answer 37

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

Question 38

Benefits of NIR for end point contact:

Answer 38

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