blending_4

Question 1

what is blending/mixing

Answer 1

produce a homogenous (ideal) mixture where all component constituents are found to be well distributed and in close contact with each other

Question 2

why blend?

Answer 2

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

Question 3

positive mix

Answer 3

complete and spontaneous mix will result by diffusion, no input of energy needed (eg. miscible liquids, gases, vapors)

Question 4

negative mix

Answer 4

phases will separate unless work like stirring is carried out (eg. insoluble particles in liquid or immiscible liquid)

Question 5

neutral mix

Answer 5

work required to mix and when stopped, will not demix spontaneously (eg. mixture of particles)

Question 6

evaluation of mix

Answer 6

1. mixed powders will always exhibit some variation in composition of samples
2. random mix will have low standard deviation, lower than mixes that have not been mixed to random state

Question 7

mixing mechanism- convective

Answer 7

• 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

Question 8

mixing mechanism- shear

Answer 8

• 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

Question 9

mixing mechanism- diffusive

Answer 9

• 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

Question 10

difference between diffusing and shear/convective mixing

Answer 10

diffusive involves individual particles, while shear and convective involves particle groups

Question 11

causative factors of segregation

Answer 11

1. difference in particle size
2. difference in particle shape
3. difference in particle density

Question 12

challenge in achieving good content uniformity

Answer 12

• 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

Question 13

general mechanism of segregation

Answer 13

1. percolation
2. elutriation
3. projection
4. feed or heap segregation
5. shear segregation

Question 14

percolation segregation

Answer 14

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

Question 15

elutriation segregation

Answer 15

air stream rushing through a powder bed will sift out the finer and/or lighter powder particles

Question 16

projection segregation

Answer 16

when a powder bed is projected into the air, the heavier particles will be projected further due to inertial forces

Question 17

feed/ heap segregation

Answer 17

heavier/larger particles will roll further down a heap of powder

Question 18

shear segregation

Answer 18

when 2 planes in a powder bed shear, the finer powder particles of the top layer will fill the voids of the bottom layer

Question 19

ordered mixing

Answer 19

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

Question 20

segregation may occur as:

Answer 20

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)

Question 21

geometric dilution

Answer 21

to thoroughly mix small amount of ingredient with larger entity

Question 22

technologies for blending

Answer 22

• drum and post hoist
• V-cone
• Y-cone
• double cone
• intermediate bulk container + pedestal type
• intermediate bulk container + post hoist type

Question 23

industrial mixers

Answer 23

• high shear mixer

- paddle, screw, agitator mixers

Question 24

common lab blenders

Answer 24

1. drum/barrel hoop blender (efficient and flexible mixing chamber change)
2. turbula mixer (best for free-flowing powders, 3D movement leads to very effective mixing)

Question 25

solid-solid mixing involves

Answer 25

1. expansion of beds of solid 2. application of 3D shear forces to powder bed 3. allow sufficient time to achieve random mix 4. maintain random state

Question 26

factors affecting mixing

Answer 26

1. % of actives: as % decreases, more difficult esp <1% ( best outcome- use random mixing and reduce particle size) 2. particle size: decrease will increase #/ weight (improve mixing potential but very small size, agglomerative, makes mixing difficult- electrostatics, frction, IMF) 3. 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) 4. particle shape: shape affect friction and flow; round easier to segregate (optimal- spherical; round easier to mix than flattish flakes, fibrous can interlock)

Question 27

important factors when testing for blend homogenetity

Answer 27

1. sample size, equivalent to unit dose 2. number of samples, ensure representation 3. sampling devices, type selected

Question 28

core sampling

Answer 28

- core/slot sampler - 3-5 sample points - sample along blend axis

Question 29

loading method

Answer 29

- should be consistent - layering reduces number of blend revolution - layer large volumes of excipient or active - lubricants dont normally require layering

Question 30

purpose of lubricants

Answer 30

use to improve flow properties and help with tableting by reducing adhesion, allows easier tablet ejection

Question 31

process variables in blending

Answer 31

1. end point determination: key measure is the number of revolutions, rather than blending time / speed 2. scale up: ~ 1:10 3. material characteristics

Question 32

material characteristics for blending

Answer 32

1. essential for excipients and base materials to be within reasonable specifications, otherwise it could lead to differing blend parameters 2. on storage, hydroscopic actives or agents can absorb moisture from excipient(s), may cause dramatic changes to blend characteristics (discharge problems/ balling)

Question 33

filling method (rotation effects)

Answer 33

1. top bottom mixing (radial mixing): v good and typically takes place in 10-20 revolutions 2. side-side mixing: longer, ~250 revolutions, indicating importance of loading

Question 34

fill level for mixing guidelines

Answer 34

20%- possible segregation 40%- takes longer than 60% 60%- optimum figure (55-70%) 80%- takes considerable longer than 40%

Question 35

powder flow issues

Answer 35

1. no flow | 2. segregation

Question 36

solution to no flow

Answer 36

internal (vibroflow) /external (frame/IBC vibration) vibration

Question 37

issues to consider for choosing vibration

Answer 37

- compaction - segregation - noise - IBC damage - Weight systems - dosing capability - product residue

Question 38

blend critical parameter

Answer 38

- number of revolution - % fill - loading method - sampling method - formulation

Question 39

benefit of near infra-red (NIR) analysis

Answer 39

- 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)

Question 40

quantitative assessment of homogenetity

Answer 40

considered homogenous when standard deviate against # rotation approaches minimum value, indicating uniform distribution of blend components

Question 41

NIR for end point control in blending

Answer 41

- 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