PHR311Pharmaceutical Engineering-I

SIZE REDUCTION AND SEPARATION

Zaki Farhad HabibWith much appreciated help from Professor Sohel Rana

Size Reduction

Definition: The reduction of materials to smaller pieces, to coarse

particles, or to powder. Alternate name for the operation is

comminution derived from the Latin minuere, meaning less.

Another name: grinding

Objectives or Purposes:

• To obtain the desired particle size. Very rarely, the materials to be

used in pharmaceutical formulations exist in the optimum size; therefore majority of them will have to be reduced to a desired

size at one stage or the other during the formulation of a dosage

form.

Application of size reduction

o Size reduction helps in rapid solution formation in the case of chemical substances by increasing the surface area of drugs.

o Extraction from animal glands (liver and pancreas) and from crude vegetable drugs is facilitated because solvent can easily penetrate into the tissues due to increase in surface area and resulting quick extraction of their active constituents.

o Therapeutic effectiveness of some drugs is increased by reducing the particle size e.g. the dose of griseofulvin is reduced to half that of originally required.

o Mixing of powders since different sized particles do not mix uniformly.

o Size reduction is very important in case of suspensions. If the size of the particles is too small, they can form a cake which may not re-disperse easily, so suitable particle size is important.

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o Size reduction is an important step of tablet production.

o In case of inhalers, appropriate particle size is crucial. Very small particles may be exhaled out of the bronchioles along with air without producing effect whereas very large ones may not even reach the alveoli and be absorbed into the blood stream.

o Size reduction improves the physical appearance of ointments, pastes and creams.

o All the ophthalmic preparation and topical preparation should be free from gritty particles to avoid irritation. So size reduction is very important.

o Increase stability of some preparation e.g. the stability of emulsion is increased by decreasing the size of the oil globules.

o Increases the rate of absorption of a drug.

o Increases the rate of drying due to exposure of larger surface area.

o To reduce the bulk of a material since shipping charges maybe based on volume.

Limitations of size reduction operation

Not suitable for all drugs e.g. drugs containing volatile oils (cinnamon, clove) must not be subjected to heavy grinding to

prevent the loss of volatile oils.

Due to increase of surface area oxidation and hydrolysis may

occur when exposed to atmospheric condition. Therefore, these drugs must be stored in a well closed container and at a cool

place.

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Factors affecting size reduction1. HARDNESS – It is a surface property of the material. Thus it is

possible for a material to be hard, but if it is brittle also, then size

reduction may present no special problem.

Moh’s Scale – arbitrary scale of hardness of mineral substances

ranging from 1 to 10. Upto 3 is soft and above 7 is hard.

Generally the harder the material the more difficult it is to reduce in size.

2. TOUGHNESS – More important property than hardness since a soft but tough material is harder to reduce in size compared to a hard but

brittle material.

Toughness can be reduced by treating the material with liquefied gas (e.g. nitrogen). At temperatures lower than -100˚C to -150˚C even

rubber becomes brittle and will break. This method is not always

employed since such low temperatures might spoil the drug and/or the materials that the machines are made of may become brittle and

break too.

3. ABRASIVENESS – A property of hard materials, particularly those of mineral origin and may limit the type of machinery that can be

used as the material being grinded can be contaminated with the

worn out material of the machinery due to high abrasiveness of the material.

4. STICKINESS – Gummy materials may adhere to grinding surfaces especially if the method used for size reduction generate heat.

Complete dryness may help.

The opposite of this, i.e. slipperiness may also pose problem to size reduction since the material acts as a lubricant and lowers the

efficiency.

5. SOFTENING TEMPERATURE – Waxy substances can soften due

to heat generated from the grinding process.

6. MATERIAL STRUCTURE – minerals may have lines of weakness,

cellular structure of vegetable drugs.

7. MOISTURE CONTENT – Amount of water a substance holds. Affects properties like hardness, toughness and stickiness. In

general materials should be dry or wet and not merely damp.

Less than 5% moisture – suitable for dry grindingMore than 50% moisture – suitable for wet grinding

8. RATIO OF FEED SIZE TO PRODUCT SIZE - If the size of original drug is too large it may be reduced to small particles in stages.

9. COST - (overall costs of process involved including power consumption, space occupied, labor expenditure and time

involved).

10. PURITY REQUIRED – may need to carry out grinding in aseptic

conditions in case it is essential to keep the material free from

bacterial contamination.

11. ENVIRONMENT – If the drug is very potent then closed mills need

to be used to reduce the drug particles spreading.

Energy requirements of size reduction process

As little as 2% of the total energy consumption is only used for size reduction process, the remainder being lost in many ways including:

• Elastic deformation of particles• Plastic deformation of particles without fracture• Deformation to initiate cracks that cause fracture• Deformation of metal machine parts• Interparticulate friction• Particle-machine wall friction• Heat• Sound• Vibration

Principle of size reduction

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A number of hypotheses and theories have been proposed in an attempt to relate energy input to the degree of size reduction produced:

1. Rittinger’s hypothesis – Energy, E used in size reduction process, is proportional to the new surface area produced, Sn

E = KR (Sn - Si)

Si is the initial surface area, KR is Rittinger’s constant of energy per unit area.

1. Kick’s Theory – Energy used in deforming or fracturing a set of particles of equivalent shape is proportional to the ratio of the change in size

E = KK log (di/dn)

KK is Kick’s constant of energy per unit mass, di is the initial particle diameter, dn is the new particle diameter

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3. Walker’s theory – generalized differential form of the energy-size relationship that can be shown to link the theories of Rittinger and Kick:

δE = - KW (δd/dn)

KW is Walker’s constant, d is a size function which could be characterized by mean size or by a weight function, n is an exponent.When n=1 for particles defined by a weight function, integration of Walker’s equation corresponds to a Kick’s type theory;when n=2 a Rittinger type solution results.

When designing milling for coarse particles > 1 µm, most appropriate value for n is 1; whereas for particles < 1 µm, value of n is 2. At n = 1.5, neither Rittinger’s nor Kick’s theory is appropriate.

None of these laws apply well in practice and are mainly of historical interest.

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Mechanism of size reduction

Cutting:

During this process the material is cut into small pieces by means of a sharp blade or any other sharp instruments.

Compression:

During this process the material is crushed by application of pressure with a suitable device.

Impact:

During impact the material which is more or less stationary, is hit by an object moving at a high speed or the moving particles strike a stationary surface and the material is broken into smaller particles.

Attrition:

During attrition the material is subjected to pressure as in the case of compression but the surfaces are in motion in relation to each-other, resulting in shear force which breaks the particles into still smaller particles.

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Methods of size reduction

Size reduction is divided into two general categories-

Manual size reduction:

• On small scale the size reduction may be carried out manually by

a) Trituration

b) Levigation

c) Intervention

Mechanical size reduction:

• Mechanical size reduction is used for large scale work which is mostly done by using different kinds of mills by milling process.

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Size reduction equipment

Selection of equipment depends on

The properties of the material to be reduced

Initial particle size

Degree of size reduction required

Various size reduction equipment are used which are

Ball mill Hammer mill

Cutter mil Fluid-energy mill

Roller mil End runner mill

Edge runner mill Hand mill

Bohr stone mill Colloid mill

Among these the most commonly used mills in pharmaceutical manufacturing are the-

Ball mill

Cutter mill

Hammer mill

Roller mill

Fluid mill

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BALL MILL

The mill which is partially filled with balls of steel or pebbles iscalled ball mill. It is also called jar mills.

Basis:

This will works on the principle of impact and attrition.

Construction:

The ball mill consists of a cylindrical container. The length of thecylinder is slightly greater than its diameter which is partially filledwith balls made from the same material as that of cylindrical vessel.The cylindrical vessel is mounted on a metallic frame and rotateshorizontally by hand or mechanically. The upper side of the vessel isfitted with a highly closed lid through which the material isintroduced.

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Mechanism of action

The material to be ground is put into the mill through the lid

↓

Rotation of the mill at a slow speed

↓

Avoid the rotation with high speed

↓

Taken out of the material from the vessel (After an appropriate time).

↓

Passing through a suitable sieve

↓

Desired particle size

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Use

1. Used for time grinding of hard, abrasive materials.

2. They can be easily sterilized therefore can be used for grinding the materials to be used in parenteral and ophthalmic preparation.

3. Used for batch or continuous operation.

Advantage

1. They are economical and simple to operate.

2. They can be used for wet and dry grinding.

3. They afford a large grinding surface within a compact space

4. A wide variety of materials can be ground with it.

5. They are easy to clean as compared to other mills.

Disadvantage

• Not applicable for soft materials.

CUTTER MILLBasis:

It works on the principle of cutting.

Construction:

Cutter mill is fitted with two types of knives i.e. stationary and rotating.

The stationary knives are mounted in the casing of the machine and at the lower part of the machine a screen of desired size is attached.

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Mechanism of Action

Feeding of particle

↓

Milling through the movement of rotating knives against stationary knives.

↓

Size reduction occurs by fracture of particles between two sets of knives.

↓

The screen retain the particles until a sufficient degree of size reduction

occurs.

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Use

Used to obtain a coarse degree of size reduction of soft materials such as roots and peels before its extraction.

Used for crude animal & vegetable drugs.

Limitations

Not used for friable materials.

The feed size should be less than 1 inch thick & should not exceed the length of the cutting knife.

The material is pre-milled and is usually suspended in a stream of air or liquid when fed to the mill.

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HAMMER MILL

The hammer mill is an impact mill using a high speed rotor up to 10,000 rpm to which a number of swinging hammers are mixed.

Basis:

It works on the principle of impact.

Construction:

The hammer mill consists of a steel casing in which a central shaft is enclosed to a number of swinging hammers are attached. On the lower part of the casing a screen of desired size is fitted. In this mill there is also-

• Hopper

• Product Outlet

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Mechanism of Action

Milling the hammers

↓

Swing out radially undergo brittle fracture (because, angular velocity of the hammers is so high, 80s-1)

↓

Continuous particle size reduction occurs (Here, the particles, are reduced by hitting the hammer)

↓

Particles are retained by the screen & passing through the meshes.

↓

Obtain the desirable particle size.

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Advantage

• They are simple to install and operate, the operation is continuous.

• They are rapid in action and many different types of materials can be ground with them.

• There is no chance of contamination due to abrasion of metal from the mill because no surfaces of the mill move against each other.

• The particle size of the material to be reduced can be easily controlled by changing the speed of the rotor, hammer type, shape & size of the screen.

• They are easy to clean and may be operated as a closed system to reduce dust and explosion hazards.

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Disadvantage

• A hammer mill must be operated with internal or external classification to produce ultra fine particles.

• Cannot be used for abrasive material.

Use

• In pharmaceutical industry they are used for grinding dry materials, wet filter cakes, ointments and slurries.

• Can be used for granulation and close control of the particle size of powders.

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Size separation

Definition :

Size separation is a process by which particles are separated into fraction of known particle size.

For pharmaceutical purpose various types of powders separated through various types of sieves.

British pharmacopoeia states that the degree of coarseness or fineness of a powder is differentiated & exposed by the size of the mesh of the sieve though which the powder is able to pass.

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Objectives of size separation

• In pharmaceutical field, the objectives of particle size separation is to separate the drug materials according to our desired size or requirements.

• In solid separation process, powered particles are removed from gases or liquids and has two main aims

To recover valuable products or by

products

To prevent environmental pollution

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The B.P. specifies five grades of powder are –

Grade of powder Sieve through which all particle must pass

Coarse………………………………………………………….10

Moderately coarse……………………………………….22

Moderately fine…………………………………………..44

Fine……………………………………………………………..85

Very fine……………………………………………………..120

Number of Sieves:

• This is the number of meshes in a length of 25.4 mm (1in.) in each direction parallel to the wires.

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Size Separation Methods

• Size Separation by sieving:

Sieving method

• Size separation by fluid classification

Sedimentation methods

Elutriation methods

Cyclone methods

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Fluid Classification

Principles of operation

Sedimentation methods are based on the measurement of the rate at which particles of the powder settle out from a liquid in which they have been dispersed.

This method is based on the dependence of the rate of sedimentation of the particles on their size as expressed by stock’s equation:

dstokes = √ 18η/(ρ-ρ0)g.x/t

Where,

dstokes = Effective or stoke diameter

η =Viscosity of the dispersion liquid.

x/t = Rate of the sedimentation.

g = Gravitational constant.

ρ = Density 1of the particles.

ρ0 =Density of the medium.

This equation applies strictly only to dilute dispersion where the concentration of the solids does not exceed 2% w/w.

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Sedimentation Equipment

The simplest method is the pipette method which is known as Andreasen method.

Construction

The apparatus used for this purpose is known as Andreasen apparatus, which consist of a fall vessel called sedimentation vessel having capacity of 500 ml.

The vessel is fitted with ground glass joint through a 10ml pipette fitted with two way stop cock for draining sample is passed.

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Mechanism

A 1% suspension of the powder in a suitable liquid medium is placed in the sedimentation vessel.

↓

At given intervals of time, samples are withdrawn from a specified depth without disturbing the suspension

↓

The samples are dried & residues are weighed

↓

By means of Stoke’s equation, the particle diameter corresponding to each interval of time is calculated.

Elutriation methodPrinciple:

Elutriation is a technique in which the fluid flows in an opposite directionto the sedimentation to the movement.

Therefore in the case of elutriation particles are divided into different sizefraction depending on the velocity of the fluid.

Mechanism

Separation of powders into several size fractions can be effected by usinga number of elutriators connected in series.

The suspension is fed into the bottom of the narrowest column,overflowing from the top into the bottom of the next widest column andso on.

Because the mass flow remains the same, as the column diameterincreases and therefore particles the fluid velocity decreases andtherefore particles of decreasing size will be separated.

Fig: Multistage elutriator. Particle Outlets 1 to 4 Collect Fraction of Decreasing Particle Size

Comparison of sedimentation & elutriation

• In sedimentation method the fluid is stationary & the separation of particles ofvarious sizes depends on particles velocity.

• In elutriation method the fluid flows & the separation of particles depends onthe velocity of the fluid.

Cyclone separation

Principle:

Cyclone separation is a form of sedimentation.

But instead of gravitational force the centrifugal force is used.

Structures

It consist of cylindrical vessel with a conical base fitted witha tangential inlet and a fluid outlet and at the base it isfitted with solids outlet.

Mechanism

The suspension is introduced tangentially at a high speed resulting a rotary movement inside the vessel

↓

The fluid is removed by the fluid outlet fitted at the top.

↓

The rotary movements within the cyclone causes the particles to move by centrifugal force

↓

The solids are thrown out to the walls of the cyclone from where they fall to the conical base and ultimately removed from there through

the solids outlet.

Application

Cyclone separators used for separating suspension of solid in liquidsbut preferably they are used for suspension of solid in a gas usuallyair.

Selection of a size separation process

Selection may be limited by pharmacopoeial requirements,but for general cases the most efficient method should beselected based on particles properties.

Among particles properties, size is particularly important aseach separation method is most efficient over a particularsize range.

Particles that have undergone size reduction will already bein suspension in a fluid, and can be separated quickly byelutriation or cyclone separation method.

Many pharmaceutical powders are soluble in water and sizeseparation may have to be restricted to air classificationmethod.