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.