Particle size Reduction

Particle size
Basic principle
1.

The study of particle sizes are important in achieving optimum

production of efficacious medicine.

2.

Virtually all of the solid materials which are in common use--> in a

powder/ granular form.

Examples
1.

Pharmaceuticals ( drugs a+ excipients could be powder handling)

2.

foods ( grain, flour, sugar)

3.

Materials technology ( Ceramics , abrasive)

4.

building materials (sane + cement)

* Uses of powders in pharmacy

Example 1

The bioavailability of poorly soluble drugs exhibiting dissolution

rate-limited absorption can be influenced by the state of subdivision
of the drug ( like Griseofulvin)

Particle size reduction leads to increased surface are per unit

weight and faster dissolution rate.

Specific surface area --> is when a solid is meassured the total

surface area per unit of mass 1. Surface area divided by the
volume or 2, Surface area divided by the mass.

--> the reduction in particle size to improve rate of dissolution and

bioavailability is not always benefical because, for example, the
toxicity effect of nitrofurantoin
Exampe 2

In inhalation aerosole, particle size is critical to achieve maximum

penetration and deposition into the deeper airway of the drug.

it has been estimated that 85% of particles >5 um are retained in the
upper respiratory tract ; 90% of particle in the 1-5um range are
retained in the alveolae . Particles <0.5um>

Example 3

Drug particle size influences the content uniformity of low dose

drugs in solid dosage forms --> tablets and capsules

Partiicle size reduction increase the number of particles per gram. -->
the greater the number of particles per dose, the lower the variability
between dosage units

Example 4

Both the physical stability and bioavailability of suspension can be

related to the particle size achieved in the product.

Sedimentation rate is proportional to the particle size ( Stoke's law)

--> is a law describing that when a resisiting force on a particle
movthing through a viscous fluid and shown a maximum is reached
in such case.

The large surface area (SA) of finely divided suspended insoluble or

poorly soluble drug ensures a high availability for dissolution -->
hence absorption

Example 5

The mechanical irritation of topical ( cream or ointment) applied to

diseased or traumatized tissues is a function of particle size.
--> a common '' rule of thumb '' is that particles should pass through
325 mesh sieve ( 44um) to minimise mechanical irritation.

Example 6

Good flowability is essential to ensuring uniform feeding of

formulations to high speed tablet machines and capsule filling
machines.--> determines uniformity of tablet and capsule weights
( and uniformity of doses, assuming uniformity mixing of drug and
excipients had been achieved )
--> smaller particles with high SA do not flow as well as larger
particles. * the greater the SA, the more dominant are surface
interactions * ( friction, cohesion/adhesion) that interact with flow.

Irregular shapes do not flow as well as very smooth shapes ( soft

particles)

Significant effect of particle shape.

1.

effect on product quality

2.

more angular materials had a greater weight variations

3.

tablets made with more angular materials had highter strength -->
increase in particle interlocking

4.

better flow will occur with spherical particles

Particle Size
Micromeritics : The science and technology of small particles

Colloidal dispersions particles : are too small to be seen in the

ordinary microscope

unit of particle size used most frequently in um = 10-6 m = 10-4 cm

= 10-3 mm

Comminution : Is an alternatve name for particle size reduction

derived from the latin minuere meaning less, but size rediction is to
be preferred as a more straightforward title

Crushing, disintegration, dispersio, grinding and pulverization have

been used synonymously with comminution depending on the
product, the equipment and the process

Why is important?
Because it helps to improve the existing active ingredients to be delieved.
Particle size influences the performance if the medicine and the
pharmacological performance of the drug. For example, powder with
different sizes have different flow and packing properties, which alter the
volumes of powder during each encapsulation or tablet compression event.
Therefore, to avoid this problem, the particle size of drug may be defined
during formulation. Because, if there are any interferences with the
uniformityof a fill volumes may alter the mass of drug that incorporated
into the tablet or capsule and hence reduce the content uniformity of the
medicine.
The following factors are infuencing size reduction

Brittle ( How easy that a particle cracks) - Crack propagation and

Toughness

Plasticity - stickiness

surface hardness - Slipperiness

melting point

Glass transition temperature

environmental factor- moisture ( To be continued)

Crack propagation & toughness

Comminution is carried out by a process of crack propagation,

whereby localised stresses produce strains in the particles, which are
larger enoug to cause bond rupture and propagate the crack - Cracks
are generally propagated through regions of a materials that possess
flaws or discontinuities and are related to the strain energy in specific
regions according to Griffith's theropy of crack propagation

Following crack initiation, crack tip propagate so rapidly- velocity

~ 40% of the speed of sound in the solid --> This crack propagation
is so rapid that excess energy from strain relaxation is dissipated
through the material and concentrates at other discontinuties, where
new cracks are propagated.

Thus, a cascade effect occur and almost instantaneous brittle

fracture occurs

Are all materials exhibit brittle behaviour? - Not all materials exhibit this
type of brittle behaviour and some can resist fracture at much larger
stresses.
why some materials can resist fracture at much larger stress? - because
these tougher materials can undergo plastic flow, which allow strain energy
relaxation without crack propagation. When plastic flow occurs, atoms or
molecules slip over one another and this process of deformation requires
energy.
* Thus, the ease of comminution depends on the brittleness or placticity of
the material because of their relationship with crack initiation and crack
propagation.
Surface hardness
- Size reduction may be influenced by surface hardness. The hardness of a
material can be described by its position in a scale devised by a German
mineralogist called Mohs.
- Mohs's scale is a table of materials :
1.

at the top of the table is diamond, which Mohs hardness > 7 , and
this has a surface that is so hard that it can scratch anything below it.

2.

At the bottom of the table is tale, with Mohs hardness <3,>

3.

Materials such as Rubber which are soft under ambient condition.

4.

Waxy substances such as stearic acid which soften when heated

5.

Stick substances such as gums are capable of absorbing large

amounts of energy through elactic and plastic deformation without
crack initiation and propagation- This type of material, which resist
comminution at ambient or elevated temperature can be more easily
size reduced by lowering the temperature below the glass transition
point of the material. When it is done, brittle behaviour and crack
propagation is facilitated. Toughness - it is often more important than
hardness

problems in size reduction: it relates to moisture content in the

material. ( compare green twig with dry one)

toughness can be reduced by treating the material with liguid

nitrogen

Freezing the material below its glass transition temperature - be

aware: the material may melt into waxy substance. ( the mill can be
cooled with water jacket or by passing a stream of air through the
mill.

Stickiness : because of heat - complete dryness and addition of inert

substances like kaolin may help
Slipperiness : the reverse of stickiness property like the lubricant effect
of materials, magnesium stearate.
Environmental factor

Moisture content of the feed material , which are material is dry or

wet but not damp.
- Moisture content <>

- Moisture content >5 % is suitable for wet milling.

Energy requirement of size reduction process

- only a very small amount of energy affects size reduction (~2%) . the
remainder is lost in many ways.

Elastic and plastic deformation without fracture

Deformation to initiate cracks that cause fracture

Deformation of metal machine parts

inter particle friction and particle -machine wall friction

Heat

Sound

vibration

Criteria for size reduction

An ideal crusher :

a large capacity

require a small power input per unit of product

Yield a product of the single size distribution desired

* The cost of power is a major expense in comminution, so the factors that

control this cost are important - To be continued
Milling Equipments
Cutting Methods

Cutter mill ( C mill)

Compression Methods

Morter and pestle

(M & P )

End-runner mill (End Mill)

Edge-runner mill ( Edge Mill)

Impact methods

Hammer Mill (H mill)

Vibration Mill (V mill)

Attrition Methods

Roller Mill (R Mill)

Combined impact and attrition methods

Ball Mills (B mill)

Fluid energy mill ( FE mill)

C mill consists of a series of knives

1.

- Size reduction occurs by fracturing particles between stationary and

rotating knives

2.

- a screen is fitted to retain the material in the mill until a sufficient

degree of size reduction is reached.

M & P - End/ Edge mill

End-runner - the pestle is turned by the friction of material passing

beneath it as the mortar rotates under power

Edge-runner- the pestle mounted horizontally and rotate against the

powder bed.

H mill - different shapes are available : Square-faced. tapered to a cutting

edge, stepped form.
Priniciple :

During milling - the hammer swing out radiallly from rotating shaft.
The higher velocity of the hammers cause brittle fracture to the
particles. Small particles are less prone to fracture than larger
particles

it produces powder with narrow size distributions. Particles are

retained within a mill by a screen which allows only adequately
comminuted particles to pass through.

V mill - Filled to appro. with 80% total porcelain or steel balls

During milling: the whole body of the mill is vibrated and size
reduction occurs by repeated impaction

milled particles fall through a screen at the base of the mill. the
efficiency of vibratory milling is greater than for conventional ball
miling.

R mill- use of the principle of attrition to produce size reduction of solid in

suspensions, pastes or ointment.

2 or 3 rolls ( porcelain or metal) are mounted horizontally with an

adjustable gap (~20um)

the roller rotates at different speeds , the materia is sheared as it

passes through the gap, the material is transferred from the shower to
the faster roll, from which is removed by means of a scraper.

B mill -Milling efficiency depends on:

1.

Feed : too much material - producing a cushioning effect ; too little causes loss of efficiency and abrasive wear of the mill part

2.

Size of the balls : - large balls break down the coarse feed material ,
the smaller helps to form the fine product by reducing the void space
between balls.

3.

Speed of rotation : -

Low angular velocities : little movement of the balls , so that the size
reduction is minimal

high angular velocities: the ball are thrown out of the mill wall by
contrifugal force and no size reduction occurs

at about 2/3 of critical angular velocities: centrifuging occurs, a

cascading action is produed . Maximum size reduction occurs by
impact of the particles with the balls and by attrition.

Jet / fiuld energy mill ( FE mill)

P mill

Lower cylinder rotates at high speeds against the upper fixed

cylinder

particle size reduction occurs by impaction with the pins and by

attrition between pins as the particles travel outwards under the
influence of centrifugal force.