blending_4 Flashcards
what is blending/mixing
produce a homogenous (ideal) mixture where all component constituents are found to be well distributed and in close contact with each other
why blend?
pharmaceutical dosage forms are produced as unit doses which are sub-units of a large production batch, each unit dose be of consistent volume with constant mass from bulk
positive mix
complete and spontaneous mix will result by diffusion, no input of energy needed (eg. miscible liquids, gases, vapors)
negative mix
phases will separate unless work like stirring is carried out (eg. insoluble particles in liquid or immiscible liquid)
neutral mix
work required to mix and when stopped, will not demix spontaneously (eg. mixture of particles)
evaluation of mix
- mixed powders will always exhibit some variation in composition of samples
- random mix will have low standard deviation, lower than mixes that have not been mixed to random state
mixing mechanism- convective
- insert a spatula into a powder bed and lifting a portion to be deposited elsewhere is a convective mixing action
- movement of a group of adjacent particles from one location to another within mixture
mixing mechanism- shear
- slip planes are formed in the powder mix as unstable fractions collapse and shear mixing occur at the interfaces
- changes occur in configuration of ingredients through the formation of slip planes in the mixture
mixing mechanism- diffusive
- occurs when body of powder is lifted beyond its angle of repose and particles avalanche, tumbling over each other (micromixing)
- difference in velocity of powder layers can help migrate particles from one layer to another
difference between diffusing and shear/convective mixing
diffusive involves individual particles, while shear and convective involves particle groups
causative factors of segregation
- difference in particle size
- difference in particle shape
- difference in particle density
challenge in achieving good content uniformity
- substantial risk of segregation at different steps of feeding process from hopper to feeder
- tendency of powder to segregate increases when there is large difference in form, size, and or density
general mechanism of segregation
- percolation
- elutriation
- projection
- feed or heap segregation
- shear segregation
percolation segregation
when a powder bed is subject to movement or vibration (eg. dilation of bed and increased particle movement), finer and/or denser powder particles will percolate to the bottom
elutriation segregation
air stream rushing through a powder bed will sift out the finer and/or lighter powder particles
projection segregation
when a powder bed is projected into the air, the heavier particles will be projected further due to inertial forces
feed/ heap segregation
heavier/larger particles will roll further down a heap of powder
shear segregation
when 2 planes in a powder bed shear, the finer powder particles of the top layer will fill the voids of the bottom layer
ordered mixing
if fine particles are mixed with coarser (carrier) particles, the fines may coat the carrier and form relatively stable blend which will not segregate.
such mixes are terms ordered since in contrast to random mixes, the constituent particles are not independent of each other and sampling necessitates removing the host particles with their adsorbed fines
segregation may occur as:
ordered unit segregation (due to size differences, larger carrier particles have more of the adsorbed components)
- displacement segregation (addition of another component may compete for the adsorbed component, displacing them- eg. adding MgSt displaces adsorbed drug)
- saturation segregation (limited active sites on the carrier particles for adsorption and if saturated, additional fines will be prone to segregation by percolation)
geometric dilution
to thoroughly mix small amount of ingredient with larger entity
technologies for blending
- drum and post hoist
- V-cone
- Y-cone
- double cone
- intermediate bulk container + pedestal type
- intermediate bulk container + post hoist type
industrial mixers
- high shear mixer
- paddle, screw, agitator mixers
common lab 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)
solid-solid mixing involves
- expansion of beds of solid
- application of 3D shear forces to powder bed
- allow sufficient time to achieve random mix
- maintain random state
factors affecting mixing
- % of actives: as % decreases, more difficult esp <1% ( best outcome- use random mixing and reduce particle size)
- particle size: decrease will increase #/ weight (improve mixing potential but very small size, agglomerative, makes mixing difficult- electrostatics, frction, IMF)
- particle size distribution: affect packing and bulk density (densely packed, more difficult to mix => narrow size distribution flow and mix better but prone to segregation post-mix)
- particle shape: shape affect friction and flow; round easier to segregate (optimal- spherical; round easier to mix than flattish flakes, fibrous can interlock)
important factors when testing for blend homogenetity
- sample size, equivalent to unit dose
- number of samples, ensure representation
- sampling devices, type selected
core sampling
- core/slot sampler
- 3-5 sample points
- sample along blend axis
loading method
- should be consistent
- layering reduces number of blend revolution
- layer large volumes of excipient or active
- lubricants dont normally require layering
purpose of lubricants
use to improve flow properties and help with tableting by reducing adhesion, allows easier tablet ejection
process variables in blending
- end point determination: key measure is the number of revolutions, rather than blending time / speed
- scale up: ~ 1:10
- material characteristics
material characteristics for blending
- essential for excipients and base materials to be within reasonable specifications, otherwise it could lead to differing blend parameters
- on storage, hydroscopic actives or agents can absorb moisture from excipient(s), may cause dramatic changes to blend characteristics (discharge problems/ balling)
filling method (rotation effects)
- top bottom mixing (radial mixing): v good and typically takes place in 10-20 revolutions
- side-side mixing: longer, ~250 revolutions, indicating importance of loading
fill level for mixing guidelines
20%- possible segregation
40%- takes longer than 60%
60%- optimum figure (55-70%)
80%- takes considerable longer than 40%
powder flow issues
- no flow
2. segregation
solution to no flow
internal (vibroflow) /external (frame/IBC vibration) vibration
issues to consider for choosing vibration
- compaction
- segregation
- noise
- IBC damage
- Weight systems
- dosing capability
- product residue
blend critical parameter
- number of revolution
- % fill
- loading method
- sampling method
- formulation
benefit of near infra-red (NIR) analysis
- no operator contact (safety)
- no sampling error (no thief)
- real time info
- multi-ingredient uniformity
- process understanding
- process finger (printing for scale up)
- right first time
- fast release of blend (reduce cycle time)
quantitative assessment of homogenetity
considered homogenous when standard deviate against # rotation approaches minimum value, indicating uniform distribution of blend components
NIR for end point control in blending
- replace conventional sampling method which is more laborious yet less sensitive, more intrusive and possibly biased
- replace use of rpm or process time to determine end point of subsequent blending runs
