Mixing

– Chapter 5

There are very few pharmaceutical products that contain only one

component. In the vast majority of cases several ingredients are

needed so that the required dosage form functions as required.

If, for example, a pharmaceutical company wishes to produce a

tablet dosage form containing a drug which is active at a dose of 1

mg, other components (e.g. diluents, binders, disintegrants and

lubricants) will be needed both to enable the product to be

manufactured and for it to be handled by the patient.

Whenever a product contains more than one component a mixing or

blending stage will be required in the manufacturing process.

Importance of mixing

List of products that invariably utilize mixing processes:

Tablets, capsules, sachets and dry powder inhalers -

mixtures of solid particles (powder mixing)

Linctuses - mixtures of miscible liquids

Emulsions and creams - mixtures of immiscible liquids

Pastes and suspensions - dispersions of solid particles.

Importance of mixing

Theoretical definition:

an operation in which two or more components in separate or

roughly mixed conditions are treated, so that each particle lies as

nearly as possible in contact with a particle of the other ingredients

>>> if this is achieved, it produces a theoretical “ideal” situation, i.e.

a perfect mix. This situation is not normally practicable.

Objective of mixing:

To obtain mixture that when divided into subunits, 1 each subunit will

contain the same quantity of a given component and 2 the same

ratio of components in the entire mixture.

Definition and objective of mixing

To simplify the discussion of the principles of mixing, we will be

considering a system consisting of equal quantities of two

constituents A (white squares) and B (black squares) of the same

size and shape.

Before mixing starts the system may be represented by the

following figure which shows the particles in a completely

segregated state.

Complete segregation (unmixed)

The mixing process

The theoretical end point of mixing is the formation of a perfect mix where

each particle lies adjacent to a particle of the other component.

The statistical probability of achieving such a perfect mix is so minute that

the best attainable mix, regardless of the method of mixing or time of

mixing, is a random mix.

An ideal or “perfect” mix

A random mix

The mixing process

Ideal (perfect) mixing is in accordance with the previous

theoretical definition of mixing, while random mixing is not.

However, random mixing can achieve the objective of mixing

depending on the final unit dose size.

In contrast to the ideal mixing, random mixing can be

achieved practically.

The mixing process

Segregation is the opposite effect to mixing, i.e. components

tend to separate out.

Segregation happens during or after mixing (due to handling or

pouring).

This is very important in the preparation of pharmaceutical

products, because if segregation occurs, a mix may change

from being random to being non-random, or a random mix may

never be achieved.

Segregation

Segregation arises because powder mixes encountered

practically are not composed of mono-sized spherical particles,

but contain particles that differ in size1, shape2 and density3.

These variations mean that particles will tend to behave

differently when forced to move and hence, tend to separate.

Particles exhibiting similar properties tend to congregate

together, giving regions in the powder bed which have a higher

concentration of a particular component.

Segregation

1. Scale of scrutiny

2. % of the active ingredient

3. Particle size

4. Particle size distribution

5. Particle shape

6. Particle density

7. Mixing time

Factors affecting mixing

1. Scale of scrutiny

Often a mixing process produces a large 'bulk' of mixture that is

subsequently subdivided into individual dose units (e.g. a tablet,

a capsule) and it is important that each dosage unit contains

the correct amount/concentration of active component(s).

It is the weight of the dosage unit that dictates how closely the

mix must be examined/analysed to ensure it contains the

correct dose/concentration.

This weight is known as the scale of scrutiny and is the amount of

material within which the quality of mixing is important.

Factors affecting mixing

1. Scale of scrutiny

For example, if the unit weight of a tablet is 200 mg then a 200

mg sample from the mix needs to be analysed to see if mixing

is adequate; the scale of scrutiny is therefore 200 mg.

If a larger sample size than the scale of scrutiny is analysed this

might mask important micro-nonuniformity.

This may lead to the acceptance of an inadequate mix

(see example in next slide)

Factors affecting mixing

1. Scale of scrutiny

Let’s imagine that the aim is a 50% drug (grey)/ 50% excipient

(white) mixture.

Factors affecting mixing

In total 400 particles: 200 particles grey, 200

white (Adequate mixing – 50% drug/50%

excipient).

Within the red block however: 6 particles

are white and 19 are grey (24% excipient

/76% drug Inadequate mixing!!)

Within the green block: 6 particles are grey

and 19 are white (24% drug/76% excipient-

Inadequate mixing!!)

1. Scale of scrutiny

In conclusion:

As the weight of the dosage unit is increased while fixing other

parameters (such as percentage of the active ingredient)

achievement of adequate mixing will be easier. This is

because the size of the scale of scrutiny will increase.

Example: it is easier to achieve more homogenous mixing

for 1000 mg tablets, than for 100 mg tablets (both

containing the same mixture).

Factors affecting mixing

Factors affecting mixing 2. % of the active ingredient

As the percentage is decreased the mixing process becomes

more difficult. Potent drugs with percentage less than 1% present

mixing problems.

To improve mixing for potent drugs:

Geometric (serial) dilution.

Factors affecting mixing

3. Particle size

Reduction of particle size will increase the number of particles

per dosage unit and lead to improvement in achieving

homogenous mixing.

However, too much size reduction would lead to particle

agglomeration due to the increase cohesion that occurs with

smaller particle. This would reduce the ease of mixing.

Factors affecting mixing 4. Particle size distribution: A. In case of broad particle size distribution: the smaller particles occupy

interstices between the larger particles, creating a more densely

packed powder. Densely packed powder usually flows with difficulty.

Accordingly, the narrower the particle size distribution the better the

flow and the easier the mixing.

Narrow particle

size distribution

Less densely

packed powder

Good flow

Easy mixing

Broad particle size

distribution

More densely

packed powder

Bad flow

Difficult mixing

Factors affecting mixing 4. Particle size distribution:

B. Wide particle size distribution can lead to segregation during or after

mixing. Two most common types of segregation: percolation

segregation and trajectory segregation.

I. Smaller particles tend to fall through the voids between larger

ones and so move to the bottom of the mass. This is known as

percolation segregation.

Factors affecting mixing 4. Particle size distribution: II. During mixing, larger particles will tend to have greater kinetic

energy imparted to them (owing to their larger mass) and

therefore move greater distances than smaller particles before

they come to rest. This may result in the separation of particles

of different size, an effect referred to as trajectory segregation.

Factors affecting mixing 5. Particle shape:

Good powder flow can lead to good mixing, but also segregation

(demixing).

Spherical particles:

→ optimum flow: good mixing, but possible segregation.

Interlocking shape (irregular) or fibrous configuration or needle-like

shapes:

→ poor flow: more difficult to mix, but less segregation once mixing

as occurred.

Size reduction of these shapes can be useful in order to change

the shape into more rounded ones.

Factors affecting mixing

Factors affecting mixing 6. Particle density

If components are of different density, the more dense material

will have a tendency to move downwards even if the particle

sizes are similar.

Trajectory segregation may also occur with particles of the

same size but different densities, owing to their difference in

mass.

Often materials used in pharmaceutical formulations have

similar density values and density effects are not generally too

important.

Factors affecting mixing

7. Mixing time

1. Non-segregating mixes will improve with continued increases in

mixing time.

2. This may not, however, occur for segregating mixes, where

there is often an optimum mixing time.

This is because the factors causing segregation generally

require longer to take effect than the time needed to

produce a reasonable degree of mixing. It is therefore

disadvantageous to prolong the mixing time beyond an

optimum point.

Factors affecting mixing How segregation can be minimized?

1. Achieving drug and excipients of the same narrow particle size range

either by:

Selection of particular size fractions for all components.

Milling of coarser components.

2. Selection of excipients which have a density similar to the active

component.

3. Selection of an optimum mixing time.

4. Reducing the extent to which the powder mass is subjected to vibration or

movement after mixing.

Mechanism of powder mixing

There are three main mechanisms by which powder mixing

occurs:

1. Convection.

2. Shear.

3. Diffusion.

1. Convection (macroscopic mixing)

It happens when there is the transfer of relatively large groups of

particles from one part of the powder bed to another, as might

occur when a mixer blade or paddle moves through the mix, for

example.

This type of mixing contributes mainly to the macroscopic mixing of

powder mixtures and tends to produce a large degree of mixing

fairly quickly.

Mixing does not, however, occur within the group of particles moving

together as a unit, and so in order to achieve a random mix an

extended mixing time is required.

Mechanism of powder mixing

Mechanism of mixing for powders

1. Convection

Mechanism of mixing for powders

2. Shear (macroscopic mixing)

Shear mixing occurs when a 'layer' of material moves/flows

over another 'layer'.

This might be due to the removal of a mass by convective

mixing creating an unstable shear/slip plane, which causes the

powder bed to collapse.

Mechanism of mixing for powders

3. Diffusion (microscopic mixing)

When a powder bed is forced to move or flow it will 'dilate', i.e. the

volume occupied by the bed will increase. This is because the powder

particles will become less tightly packed and there is an increase in

the air spaces or voids between them. Under these circumstances

there is the potential for the particles to fall under gravity, through the

voids created.

Mixing of individual particles in this way is referred to as diffusive mixing.

Shear and convective mixing can quickly produce a rough mix but

local groups of particles may remain unseparated unless subjected to

diffusive mixing.

Mechanism of mixing for powders 3. Diffusion (microscopic mixing)

Ordered mixing It would be expected that a mix comprised of very small and

much larger particles would segregate because of the size

differences.

Sometimes, however, if one powder is sufficiently small

(micronized) it may become adsorbed on to the 'active sites' on

the surface of a larger 'carrier' particle and exhibit great

resistance to being dislodged.

The phenomenon is referred to as ordered mixing.

This has the effect of minimizing segregation while maintaining

good flow properties.

Ordered mixing Order mixing, occurs to a certain extent in every pharmaceutical powder

mix, owing to interactions and cohesive/adhesive forces between

constituents. However, it is most likely to occur when smaller particles exist.

Pharmaceutical mixes are therefore likely to be partly ordered and partly

random, the extent of each depending on the component properties.

With an ordered mix it may be possible to achieve a degree of mixing which

is superior to that of a random mix, which may be beneficial for potent drugs.

Note: although ordered mixes can reduce or prevent segregation, segregation

may still occur!

Ordered mixing

Example: Dry powder inhaler formulations use ordered mixing to deliver

drugs to the lungs.

Drug and carrier are mixed to produce an ordered mix.

In this case the drug needs to be in a micronized form (generally <5 µm) in

order to reach its site of action.

The carrier (generally α-lactose monohydrate) has a median size generally

between 30-150 µm.

The powder flows easily out of the inhaler (due to size of the carrier particles)

Once liberated from the inhaler de-aggregation of the drug-carrier

aggregates occurs.

Design

Tumbling mixers are commonly used for

the mixing/blending of granules or free-

flowing powders.

There are many different designs of

tumbling mixer, e.g. double-cone mixers,

twin-shell mixers, cube mixers, Y-cone

mixers and drum mixers.

Tumble mixer can be with or without

agitator mixing bar (or blade)

Tumbler mixers

Mixing containers are generally mounted so that they can be

rotated about an axis.

V-shape blenders(to right) and Double cone (to left)

Tumbler mixers

Mechanisms of mixing

When operated at the correct speed, the tumbling action is achieved.

Shear mixing will occur as a velocity gradient is produced, the top

layer moving with the greatest velocity and the velocity decreasing as

the distance from the surface increases.

When the bed tumbles, it dilates, allowing particles to move

downwards under gravity, diffusive mixing occurs.

Tumbler mixers

Too high a rotation speed will cause the material to be held on

the mixer walls by centrifugal force and too low a speed will

generate insufficient bed expansion and little shear mixing.

Tumbling mixers are available to mix from approximately 50 g,

e.g. for laboratory-scale development work, to over 100 kg at a

production scale.

The material typically occupies about a half to two thirds of the

mixer volume.

Addition of baffles or rotating bars will also cause convective

mixing (e.g. the V-mixer with agitator bar or blade).

Tumbler mixers

Applications

Tumbling mixers without agitator bar are good for free-flowing

powders/granules.

Unsuitable for cohesive/poorly flowing powders, because the shear

forces generated are usually insufficient to break up any aggregates.

Care must also be taken if there are significant differences in particle

size present, as segregation is likely to occur.

They mix powders with minimal energy imparted to powder bed:

→ they cause minimal size reduction (suitable for material that tend

to fracture).

Tumbler mixers

In pharmaceutical products manufacturing, it is often

preferable to use one piece of equipment to carry out more

than one function.

An example of this is the use of a mixer-granulator. As the

name suggests, it can both mix and granulate a product.

High-speed mixer granulator

The centrally mounted impeller blade at the bottom of the mixer rotates

at high speed, throwing the material towards the mixer bowl wall by

centrifugal force.

The material is then forced upwards before dropping back down

towards the centre of the mixer.

The particulate movement within the bowl tends to mix the components

quickly owing to high shear forces1 (arising from the high velocity) and

the expansion in bed volume that allows diffusive mixing2.

High-speed mixer granulator

Once mixed, granulating agent can be added and granules

formed in situ.

Applications:

Because of the high-speed movement within a mixer-

granulator, care must be taken if material fractures easily (i.e.

there might be unwanted particle size reduction).

This type of mixer is not normally used for blending lubricants

(due to risk of fracture for the particles).

High-speed mixer granulator

This type of mixer depends on the motion of a blade or paddle

through the product, and hence the main mixing mechanism

is convection.

Examples include:

the ribbon mixer.

the planetary mixer.

the Nautamixer.

Agitator mixers

Ribbon mixer

Mixing is achieved by the rotation of helical blades in a

hemispherical trough.

The ribbon mixer is top-loading, with bottom discharge port.

Agitator mixers

Ribbon mixer

It has a major disadvantage: the possibility of dead spots (areas

that remain unmixed) at the ends and in the corners of the

mixer.

Moreover the shearing action caused by the movement of the

blades may be insufficient to break up drug aggregates

(unsuitable for cohesive powders).

Applications:

Suitable for poorly flowing materials.

It is less likely to cause segregation than a tumbling mixer.

Agitator mixers

Nautamixer

The Nautamixer consists of a conical vessel

fitted at the base with a rotating screw, which

is fastened to the end of a rotating arm at the

upper end.

The screw conveys the material to near the

top, where it cascades back into the mass.

The mixer thus combines convective mixing1

(as the material is raised by the helical

conveyor) and shear2 and diffusive mixing3

(as the material cascades downwards)

Agitator mixers

Planetary mixer

Similar designs are used for both powder

and semi-solid mixing.

The bowl is raised up to the mixing blade for

the mixing process.

The mixing blade is carried on a rotating

arm.

It therefore travels round the circumference

of the mixing bowl, while simultaneously

rotating around its own axis.

Agitator mixers

This is therefore a double rotation

similar to that of a spinning plant

planet around the sun. From this the

name “Planetary mixer”.

Agitator mixers

Planetary mixer

Testing for blend homogeneity

This is usually done when one is developing a new formula and

procedure for a product and during scale up.

This is particularly true in case of expecting mixing problems

such as potent drugs.

Three issues must be considered:

A. Sample size: try to make your sample size equal to unit size.

For example if you testing a formula to be compressed to

tablets of 800 mg, then sample size of approximately 800 mg is

a good choice.

Testing for blend homogeneity

B. Number of samples: the larger the number of samples

taken from different locations, the more representative is the

sampling. One way to take samples is to view the powder

bed as three layers (top, middle and bottom) and each layer

is divided to into three locations: right, center and left. Taking

samples from the 9 locations is a reasonable way.

C. Sampling devices: There are two common sampling

devices

Testing for blend homogeneity

There are two common sampling devices:

A. Scoop: It has disadvantages:

Scooping cannot remove a sample from the middle or bottom of a

blender without considerable disturbance of the mixture.

Scooping from the top of powder may produce samples that were

segregated on standing.

B. Thief sampler: This is the most common device, which permits you to

take samples deep within the mixture without considerable

disturbance. It consists of outer and inner tubes.

Testing for blend homogeneity

The outer tube is pointed with openings at the bottom, middle

and top. The inner tube has dies or sample containers at the

same location of the openings of the outer tube. It also has a

handle to rotate inside the inner tube.

Testing for blend homogeneity

Before the insertion into the powder bed for sampling, the inner tube is

aligned so that the openings and dies do not match; thus upon insertion

no powder will be filled into the dies. After insertion, the inner tube is

rotated so the openings and dies match and the product flows in and

fills the dies. Then, openings and dies are re-unmatched and the whole

device is removed from the mix.