Lecture 3- Powder Mixing

Question 1

Mixing + Rationale

Answer 1

Mixing=
-two or more ingredients in a separate or roughly mixed condition are treated so that each particle of any one ingredient is mixed to achieve a uniform distribution

Rationale=
-mixing ensures uniform composition so that small samples accurately represent the overall mixture.

Question 2

Types of mixtures:

Answer 2

*positive mixture= mixtures that completely and irreversibly mix, such as two gases/ miscible liquids

*negative mixture= any two-phase system; phases differ in density will separate unless continuously agitated e.g. solid suspended in liquid

*neutral mixture= neither mixing nor de-mixing takes place unless the system is acted on by a system of forces e.g. mixing solids with solids

Question 3

Mixing of solids

Answer 3

-mixing of all systems of matter involves a relative displacement of the particles, whether molecules/ small crystals until a stage of maximum disorder is created and a completely random arrangement is achieved

Question 4

Perfect mix

Answer 4

-each particle lay adjacent to a particle of the other component
-such an arrangement is impossible in powder
-no mixing equipment can do better than produce the random mixture

Question 5

Random + ordered mix

Answer 5

Random- probability of finding one type of particle at any point in the mixture is equal to the proportion of that type of particle in the mixture

Ordered- two components interact to form ordered units

Question 6

Scale of scrutiny

Answer 6

-amount of material within which the quality of mixing is important
-if the unit weight of a tablet is 200mg, 200mg of mixture should be assessed to see if mixing is adequate
-number of particles in the scale of scrutiny increases= sample weight, decreasing density + size of particles (however reducing the particle size too much= increases cohesion and particle aggregation = poor mixing and powder flow properties)
-number of particles should be sufficient to ensure minimal deviation in the required dose in the dosage form

Question 7

Sampling procedure

Answer 7

-number of samples; min 10
-use a sampling thief
-samples must be removed from different parts of the mixer; i.e. different depths, middle and sides
-powder bed cannot be disturbed during sampling

Question 8

Mechanisms of mixing and de-mixing

Answer 8

All 3 mechanisms take place to some extent during mixing but they vary in extent with the type of mixer used
-connective mixing
-shear mixing
-diffusing mixing
Good mix= inter-particulate movement

Question 9

Dilation of powder bed= increase in volume

Answer 9

Achieved by= voiding space within the mixing vessel
-mixing vessel should not be overfilled

Question 10

Convective mixing

Answer 10

-transferring groups of adjacent particles from one location in the mass to another
-whole volume of material is continuously divided up and then mixed again after the portions have changed places
-coarse scale dispersion
-predominates in machines utilising a mixing element moving in a stationary container

Question 11

Shear + Diffusive mixing

Answer 11

Shear- occurs when a system of forces acting on the particles induces the formation of a slip plane. This gives relative displacement of two regions

Diffusive- distributing particles over a freshly developing surface
-when a powder bed is forced to flow it will dilate - increase in volume creating the void space. The particles fall under gravity, through the voids created

Question 12

Powder segregation

Answer 12

Segregation- opposite effect to mixing
-a mix may change from random to non-random, the batch may fail a uniformity of content test
Segregation occurs when= during storage, transfer to filing machines and in the hopper of a tablet/capsule/sachet-filling machine

Question 13

Powder segregation caused by;

Answer 13

-difference in particle size, shape, density, surface and roughness
-forces of attraction
-friction
-particles with DIFFERENT properties behave differently when forced to move and tend to separate
-particles with SIMILAR properties tend to congregate together, giving regions in the powder bed= higher concentration of a particular component

Question 14

Segregation

Answer 14

Percolation segregation; smaller particles that fall through the voids between larger particles - move to the bottom of the mass
-occurs whenever a powder bed containing particles of different size is distributed

Elutriation segregation; small particles that are blown upwards by turbulent air currents as the mass tumbles and remain suspended in the air

Question 15

Segregation- effect of particle dentistry

Answer 15

-denser material tends to move downwards even if particle sizes are similar
-trajectory segregation may occur with particles of the same size but different densities

Question 16

Segregation- effect of the particle shape

Answer 16

-spherical particles are easily mixed but segregate easily due to their flowability
-irregular/needle-shaped particles= less tendency to segregate once mixing has occurred because of interlocking and greater contact surface area

Question 17

Segregation through agglomeration

Answer 17

Agglomerates form when there are strong inter-particulate forces
This results from; liquid bridges formed in solids, electrostatic forces and van der waals forces

What to do= shear forces must be employed during mixing to break up these agglomerates using high-speed impellers/knives

Question 18

Segregation through floating + how to overcome issues

Answer 18

-smaller particles flow into vacant space = preventing the larger from reclaiming its original position

Overcoming issues;
*narrowing the size distribution between drug and excipients= sieving to remove lumps + milling components together
*controlled crystallisation during production of the drug/excipients= particular crystal shape/size range
*match the density= of excipients with the active ingredient
*reduce excessive vibration = after mixing
*use filing machines hoppers= powder residence time is reduced
*avoid moisture
*use equipment where several operations can be carried out
*produce ordered mix

Question 19

Ordered mixing

Answer 19

-reduces segregation between very fine powder and larger particles

Segregation may still occur if:
-variation in particle size
-insufficient carrier particles
-subjecting the mix to excessive vibration

Question 20

Powder mixing equipment; tumbling mixers/ blenders + high-speed mixer granulators

Answer 20

*tumbling mixers/ blenders
-operate by a mainly diffusive mechanism
-suitable for free-flowing powder and granules since the shear forces generated are usually insufficient to break up any aggregates = poor choice for cohesive materials
*tumbling mixers= non-cohesive blending

*high-speed mixer granulators
*advantages; -more than one operation able to mix and granulate a product- removes the need to transfer the product between different equipment
-operate by both shear forces and diffusive mixing
*disadvantages; -not suitable for high brittle material, because of high-speed movement + blending lubricants

Question 21

Powder mixing equipment; fluidized -bed mixers + agitator mixers

Answer 21

Fluidized- bed mixers; Balance the downward gravitational forces of particle weight with the upward forces from high gas flow

Agitator mixers e.g.planetary mixer;
-main mixing mechanism= convection
-possibility of mixing poor flowing powder
-less likely to cause segregation than a tumbling mixer

Agitator mixers e.g. ribbon mixer;
-moderately low shear
-fast rotational speed= fluidization
-may segregate with free-flowing materials of different size
-fair choice for cohesive materials

Nautamixer;
-rotating screw conveys the material closer to the top (connecting mixing takes place)
-material cascade downwards into the mass (shear and diffusive mixing takes place)