SIZE REDUCTION (Comminution)

Size reduction or comminution is the process of reducing drugs (vegetable and chemical substances) into smaller pieces,coarse particles or fine powder.

Importance of Particle Size Reduction

The process of size reduction is commonly employed in pharmaceutical industries due to the following reasons:

1 To increase the rate of solution in case of chemical substances, because reduction of the particle size increases the surface area for the action of solvent .

2 To allow the rapid penetration of the solvent (menstruum ), in case of crude drugs for the extraction of active constituents from vegetable and animal drugs.

3 To get a uniform powder because particle size reduction helps in uniform mixing of drugs,required for preparing different formulations for administration.

4 To increase the rate of absorption of a drug.The smaller the particle size , the greater is the rate of absorption.

5 To improve the stability of certain pharmaceutical dosage form ,such as suspensions .The rate of sedimentation decreases to a large extent by reducing the particle size of drug.

6 To help in the process of separation of solids from liquids by filtration or by sedimentation .The rate of filtration or sedimentation depends upon the particle size.

Factor Affecting Size Reduction

The following factors affect the process of size reduction

1 Hardness :- The hardness of the material affects the process of size reduction .It is easier to break soft material to a small size than hard material.

2 Toughness: The crude drugs of fibrous nature or those having higher moisture content ,are generally tough in nature.A soft but tough material may present more problem in size reduction , than a hard but brittle substance.

3 Stickness :- Stickiness causes a lot of difficulty in size reduction.

This is due to the fact that material adheres to the grinding surfaces or sieve surface of the mill. It is difficult to power a drugs of having gummy or resinous nature,if the method used for size reduction generates heat. Complete dryness of material may help to overcome this difficulty.

4 Material structure :- Materials which show some special structure may cause problem during size reduction e.g.. vegetable drugs which have cellular structure ,generally produce long fibrous particles on its size reduction.Similarly a mineral substances having lines of weakness , produces flake like particles on its size reduction.

5 Moisture content:- The presence of moisture in the material influences a number of its properties such as hardness ,toughness or stickness which in its turn affects the particle size reduction .The material should be either dry or wet.It should not be damp.The material having 5% moisture in case of dry grinding and 50% moisture in wet grinding does not create any problem.

6 Softening temperature :- Waxy substances such as stearic acid or drugs containing oils or fats ,become softened during the size reduction processes,if heat is generated.This can be avoided by cooling the mill.

7 Purity required :- Various mills used for size reduction often cause the grinding surfaces to wear off and thus impurities come in the powder .If a high degree of purity is required ,such mills must be avoided .Moreover ,the mills should be thoroughly cleansed between batches of different material in order to maintain purity.

8 Physiological effect:- Some drugs are very potent.During their particle size reduction in a mill,dust is produced which may have an effect on the operator .In such cases,the enclosed mills may be used to avoid dust.

9 Ratio of feed size to product size:- To get a fine powder in a mill,it is required that a fairly small feed size should be used .Hence it is necessary to carry out the size reduction process in several stages,using different equipment e.g. preliminary crushing followed by coarse powder and then fine grinding.

10 Bulk density:- The output of the size reduction of material in a machine,depends upon the bulk density of the substance.

Laws governing energy and power requirements of mills
During size reduction energy is supplied to the equipment (mill). Very small amount of energy (less than 2%) actually produce size reduction. Rest of the energy is dissipated (wasted) in:
(i)               Elastic deformation of particles
(ii)             Transport of material within the milling chamber
(iii)           Friction between the particles
(iv)            Friction between the particles and mill
(v)             Generation of heat
(vi)            Vibration and noise.
(vii)          Inefficiency of transmission and motor.
Theories of milling
A number of theories have been proposed to establish a relationship between energy input and the degree of size reduction produced.
Rittinger’s theory 
Rittinger’s theory suggests that energy required in a size reduction process is proportional to the new surface area produced.
Bond’s theory
Bond’s theory states that the energy used in crack propagation is proportional to the new crack length produced.
Kick’s theory
Kick’s theory states that the energy used in deforming (or fracturing) a set of particles of equivalent shape is proportional to the ratio of change of size.

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 measured 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 beneficial because, for example, the toxicity effect of nitrofurantoin

Example 2 

• In inhalation aerosol, 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 
• Particle 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)