Blending Flashcards
Why is there a need for blending?
pharmaceutical dosage forms = each unit dose needs to be of constant volume with a constant mass from a bulk; thus need to mix well
ensure content uniformity of dosage form
definition of blending/mixing?
homogenous mixture where all components are well distributed and in close contact with each other
3 theory of mixing
positive mix, negative mix and neutral mix
what is positive mixing?
complete and spontaneous mix due to diffusion, no energy required (e.g. miscible liquids, gases, vapours)
what is negative mixing?
phase will separate unless work (e.g. stirring) is done (e.g. insoluble particles in liquids or immiscible liquids)
what is neutral mix?
work required to mix but wont demix spontaneously (e.g. mixture of powders)
what is the important type of mix for powders
neutral mix
can a random mix be ideal?
no, standard deviation will be low, but never zero
- but still the end goal at the end of blending
3 types of mixing mechanism
convective, shear, diffusive
what is convective mixing
move a group of adjacent particles from one location to another within the mixture
- insert spatula and lift portion of powder and deposit elsewhere
what is shear mixing?
slip planes formed –> shear mixing occurs at the interfaces on the shear plane
what is diffusive mixing
body of powder lifted beyond angle of repose and particles avalanche, tumbling over each other; aka micromixing
principle: diff in velocity of powder layer (concept similar to diffusion in liquids)
INVOLVES individual particles
what is an important thing to take note of diffusive mixing compared to shear and convective mixing?
diffusive mixing involves individual particles, unlike shear and convective mixing which involve particle groups
What causes segregation? (3 factors)
(1) diff in particle size
(2) diff in particle shape
(3) diff in particle density
why does segregation happen?
(1) can happen at diff steps of the feeding process from hopper to feeder (powder transfer)
(2) segregation tendency increases when there is a large difference in form, size, or density
5 mechanisms of segregation?
- percolation
- elutriation
- projection
- feed or heap
- shear
what is percolation segregation?
powder bed subjected to movement or vibration: finer powder and/or denser powder particles precolate to the bottom
seen in bins that vibrate
what is elutriation segregation
air stream rushing through a powder bed to sift out the finer and/or lighter particles
seen when empty tube filled with powder
what is projection segregation?
powder bed projected into the air; due to inertial forces, heavier particles projected further
seen in horizontal belt conveyer
what is feed or heap segregation
heavier/larger particles roll further down (away from center) a heap of powder
seen when charging (pouring) a hopper or bin
what is shear segregation?
2 planes in powder bed shear, finer powder particles at the top will fill the voids of the bottom layer
seen when powder blend flows down a slope
what is ordered mixing
fine particles are mixed with coarser (carrier) particles, where the fine particles may coat the carrier, and form a relatively stable blend which will not segregate
problems faced with ordered mixing
(1) ordered unit segregation: due to size diff, larger carrier particles have more adsorbed components; meaning more rich with drug
(2) displacement segregation: adding another component may compete for adsorbed component –> displace them
e. g. MgSt (lubricant) can displace adsorbed drug
(3) saturation segregation: limited active sites on the carrier particles for adsorption and if saturated, the additional fine particles are more prone to segregate by precolation
what is geometric dilution
in pharmaceutical mixing, mix a small amount of ingredient with a larger entity
e.g. if have small amt of drug + large amt excipient; add equal amt of excipient with the entire small amt of drug
vice versa if large amt of drug with + small amt ecipient
diff types of blending equipment
- drum and post hoist
- V-cone
- Y-Cone
- Double Cone
- IBC + Pedestal type
- IBC + Post Hoist type
V, Y, Double cone = have been replaced by IBC blenders; V, Y, double cone use for small scale
types of industrial mixers
- high shear mixer
- paddle, screw, agitator mixers
- mechanofusion
- vertical cone screw blender
- intensive agitator mixer
2 common laboratory blenders
drum/ barrel hoop blender: efficient and flexible mixing chamber change
turbula mixer
- best for free-flowing powders
- 3D movement leads to very effective mixing
What is the mixing process for solid-solid mixing?
(1) expansion of the beds of solids
(2) 3D shear forces to the powder bed
(3) allow sufficient time to achieve random mix
(4) maintain random state
What are some factors affecting mixing?
(1) % of actives
(2) particle size
(3) particle size distribution
(4) Particle shape
explain why % of active affects mixing
- as % decreases, more difficult for <1% to mix; thus random mixing and reducing particle size to be done for better outcome
explain why particle size affects mixing
as size decreases, number of particles increases –> this improves mixing
BUT at very small sizes, agglomeration, makes mixing difficult (e.g. electrostatic, friction, intermolecular forces)
explain why particle size distribution affects mixing
affects packing and bulk density; densely packed means more difficult to mix (I think broader size distribution)
narrow size distribution (mix better but prone to segregation post-mix)
soln: broader size distribution
explain why particle shape affects mixing
optimal shape is spherical as easier to mix than flattish flakes
- fibrous material can interlock and harder to mix but less prone to segregation
- round material can mix easily but more prone to segregation
Whydo we test for blend homogenity? When do we do this?
- Determine optimal mixing time
- usually used during development, scale-up phase or when changing a blender
What are some important factors affecting blend homogeneity
sample size, needs to be equivalent to unit dose
number of samples = to ensure representation
sampling devices used
What are some important factors about sampling?
-sufficient sampling points (i.e. 19 for 1000L IBC with a thief key for performance qualification (PQ))
- suitable sampling devices
- -> to avoid scooping movement (ensure no disturbance)
- -> thief keys can be inaccurate
- -> a core sample improves accuracy (rather than thief key)
benefits of a core sampler
3-5 sample points (multipoints)
sample along the blend axis
What are some important factors for loading method?
- have to be consistent
- layering to reduce number of blend revolution
- layer large volumes of excipient or active
- lubricant don’t normally require layering - just added to the top, towards the end of mixing period
- don’t over mix the lubricant
benefits of adding a lubricant in the loading method
(lubricant added to improve flow properties, and help tableting by reducing adhesion, easier tablet ejection)
What are some process variable in blending
(1) end point determination
- to measure number of revolution, rather than blending speed or time
(2) scale up
- normally 1:10 (scale up 10 times once studies are completed on a less quantity)
(3) material characteristics
- excipients and base material must be within specifications (as can affect the blending parameters)
- discharge problem/ balling if hygroscopic actives absorb moisture from excipients
guideline to ensure efficient mixing
- the filling method
top-bottom mixing (10-20 rev) better than side-side mixing (250 rev)
top-bottom = aka radial mixing
% fill ratio to be 60% (55-70%) (2/3 full)
- other % takes longer to mix
current trends on mixing
(1) containment
- contained the additions in blending room
- sampling is contained
- milling blending modules
- non-GMP production areas
- through-the-wall installation
(2) PAT (process analytical tech) - in-line monitoring with NIR system
what are the solutions available if the powder has no flow?
as no flow could lead to segregation
(1) external vibration
- frame vibration
- IBC vibration
(2) internal vibration
- vibroflow
where do we require flow to ensure no possibility of segregation
during material transfer and production stages
problems/issues of internal/external vibration
- compaction (could happen when vibrating)
- segregation
- noise
- IBC damage
- weighing systems
- dosing capability
- product residue (use a external vibrator as residue stuck to sides)
important factors of the bin when blending (key blending parameters)
.Blend critical parameters:
- number of revolution
- % fill
- loading method (layering)
- sampling methods
- formulation
.simple scale up process
.contained process
advantages of Near Infra red (NIR) analysis
- no operator contact (safe)
- no sampling errors (no thief)
- real-time info
- multi-ingredient uniformity
- understand the process
- process finger-printing for scale-up
- right the first time
- fast release of the blend –> reduces cycle time
how to assess the homogeneity in NIR?
the curves get stable and start to look the same
- standard deviation approaches minimum value
advantages of Near Infra red (NIR) analysis over the conventional sampling method
conventional sampling method: more laborious and less sensitive, more intrusive and possibly biased
NIR replaces the use of rpm or process time to determine end point of blending runs (now SD approaching minimum value is the end point)
summary: how can we determine end point mixing?
using NIR, PAT-enabled
summary: why is the blending process so impt
impt as critical for direct compression and ensure quality in solid dosage form manufacturing
summary: how do we avoid segregation issues?
- we need to understand the segregation potential and material transfer technologies
summary: what are the key blending parameters?
(1) number of revolution
(2) % fill
(3) loading method
(4) sampling methods
(5) formulation
summary: what must be produced at the end of blending?
random mix
summary: what happens when blending occurs
increase entropy of powders by applying mechanical forces (i.e. convective, shear, diffusive)
