MUCLecture 2022 3933148

Milling
1
Milling (Particle Size Reduction)
• Milling can be defined as the mechanical process of reducing
the particle size of solids.
• Most ingredients in pharmaceutical formulation’s ingredients
must be milled at some stage during the production of a dosage
form.
• The resulting particle size distribution (PSD), in most cases, is
believed to have a great impact on bioavailability and/or
downstream processes.
• However, the fundamental understanding of the process is still
limited.
• Generally, size reduction and size separation are combined to
obtain a powder with the desired particle size distribution
(PSD) which is acceptable for processing.
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MUC- School of Pharmacy- Babylon- Iraq Industrial Pharmacy I- 4th stage. – Spring 2022
Advantages of Milling
1. Dissolution, delivery and therapeutic efficacy:
a) Rate of dissolution (how fast drug goes into
solution).
• The smaller particle will have a larger specific surface
area (surface area per unit weight) that enhances dosage
form dissolution.
• This will have an impact on bioavailability.
• For example, the control in the fineness of Griseofulvin
had led to an oral dosage regimen half that of the
originally marketed product.
• This also decreases the side effect of that drug due to the
lower dose required to get the desired therapeutic action.
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Dissolution, Delivery and Therapeutic Efficacy
b) Powder flow characteristics depend on
particle size and size distribution.
c) Particle size will also affect drug
distribution into the lung. The smaller
particle can travel deeper into the lung
when administered such as aerosol.
d) Transdermal delivery is also enhanced to
some extent by reducing particle size.
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2. Drying: smaller particles with large specific surface areas will require less time
for optimum drying.
• This is because of the reduction of the distance that the moisture must travel
within the particle to reach the outer surface.
3. Powder mixing can be enhanced with particle size reduction as we mentioned
in lecture 1.
4. Formulation: such as when using a lubricant during tablet formulation that
needs to cover formulation granules. So, the finer the lubricant the better the
coverage.
• Another example is when formulation an ointment or creams where the fine
particle will provide a smooth texture and better appearance in addition to
improved physical stability.
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Disadvantages of Milling
• Excessive milling has some disadvantages in manufacturing of
pharmaceutical dosage forms such as:
1. Further reduction in particle size will cause other problems
such as particle agglomeration and poor flow properties.
2. It can also cause product instability for example increased
powder oxidation due to an increase in the surface area.
3. It may cause heat instability due to the heat-generating during
the milling process.
4. It may cause drug polymorphism and the drug may change to
an unstable form.
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Size Measurement
• Size is conventionally expressed in terms of mesh
• Mesh is the number of openings per linear inch of a
screen. ) 6 mesh
• Higher mesh number means smaller opening diameter

• So, 10 mesh is larger than 20 mesh
• Size is also expressed as a diameter which is measured in 20 mesh
𝜇m (micro meter =10-6 meter), or nm (nano meter =10-9
meter).
• Milling equipment is classified as coarse (size > 20
mesh), intermediate (size 20- 200 mesh), or fine (smaller 30 mesh
than 200mesh) according to the size of the milled product.
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Particle Size Distribution (PSD)
• Usually, solid particles have an irregular shape.
• When particle size is measured these particles are an approximate sphere shape in
order to be measured by one number which is the diameter (d).
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• In materials used in pharmaceutical
preparations, particle size can be:
1. Monodispersed when the particles have
nearly the same diameters.
2. Polydisperse when particles have different
diameters.
• The polydisperse case is more common in real
life.
• In order to study the powder properties that
have a particle with different diameters and to
compare with other products, particle size can
be represented as a histogram distribution.
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“Histogram”
• In (a) the particle is called normally distributed Normal
around a central value (the average).
• In (b) particle is called skewed (to the right or
positive in this case) where the powder sample is
said to have more fine particles. Skewed
• In (c), there is more than one mode and it is
called bimodal distribution, and usually, this
powder type is required milling to reduce the size
of the larger particles.
Bimodal
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“Cumulative distribution”
• An alternative to the histogram representation of
particle size distribution is obtained by
sequentially adding the percent frequency
values to produce a cumulative distribution.
• Powders can be compared using the cumulative
distribution, where (a) has a broader size range
than (b).
• For pharmaceutical applications (b) is regarded
as a less problematic powder.
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Particle Size Analysis Methods
• The particle size distribution in a
powder may be qualified and/or
quantified by:
1. Determining the weight of particles
such as sieving, sedimentation,
centrifugation.
2. Determining the number of
particles such as the microscopy
method.
3. Determining the volume of particles
such as coulter counter.
4. Determining light scattering by
particles such as dynamic light
scattering (DLS). 12
Particle Size Analysis
“Sieving”
• Is a widely used method for measuring particle size
distribution.
• Advantages are inexpensive, simple, and rapid
analysis method.
• The international standard organization (ISO)
determine sets the size limit to use this method by
45um to 1000um (1 mm).
• There are sieves available outside this range but
they are not approved by ISO.
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“Sieving”
• Most sieve analyses use a series, stack, or ‘nest’ of sieves.
• The smallest mesh above a collector tray followed by
meshes that become progressively coarser towards the top
of the stack of sieves.
• The powder is loaded onto the coarsest sieve at the top of
the assembled stack and the nest is subjected to
mechanical vibration.
• The disadvantage of the sieving method is that it takes
time to complete and may not be complete at all because
a particle can take a long time to orient themselves over
the sieve apertures and pass through.
• It also requires a large amount of samples.
14
“Sedimentation”
• This method is used to measure the particle size based on stock’s law
which stated that the rate of sedimentation of the particle is directly
proportional to the particle diameter as follow:
𝑑𝑥 𝐷2 𝜌 𝑝𝑎𝑟𝑡𝑖𝑐𝑙𝑒 −𝜌 𝑚𝑒𝑑𝑖𝑢𝑚 ∗ℊ 18𝜂 𝑡
• = so 𝐷 =
𝑑𝑡 18𝜂 𝜌 𝑝𝑎𝑟𝑡𝑖𝑐𝑙𝑒 −𝜌 𝑚𝑒𝑑𝑖𝑢𝑚 ∗ℊ 𝑥
• Where:
𝑑𝑥
• = sedimentation rate in (cm/s) ; D= particle diameter (cm)
𝑑𝑡
• 𝜌 = density in g/ml ; ℊ= gravity constant (980.7 cm. s-2)
• 𝜂= medium viscosity in g. cm-1 . s-1 or (poise)
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“Sedimentation”
• The sample is prepared as suspension and placed in a
graduated cylinder.
• After some time, the particle size can be measured by
measuring the distance for particle fall.
• This measurement can be done by taking samples from a
different location in the suspension (Andreasen pipette).
• Samples are then dried and weighed so that the percent from
the total can be calculated.
• The size range for this method is 1- 200 um.
• Advantages of this method are simple and economic.
• The disadvantage of this method is that at particle size below
5 um the settling time becomes very long.
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“Microscopy”
• Microscopy is a direct method for size
distribution measurement.
• Its either a light microscopy (LM), scanning
electron microscopy (SEM), or transmission
electron microscopy (TEM).
• The measurement range:
• Light microscope is 1-1000 um LM
• SEM is 5 nm – 1 micron.
• TEM can go down to 1 nm.
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“Microscopy”
• The advantage of this method is that the SEM
actual shape of the particle can be seen and
size can be measured after that.
• The disadvantages include being time-
consuming because the operator has to
measure the size of a large number of
particles. TEM
• In addition, these methods require special
sample preparation which adds cost to the
operation.
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Scanning Electron Microscopy SEM
• Apply electron beam to the sample.
• Recorded the reflected electrons
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“Electrical Sensing Zone (Coulter Counter®)”
• This method can be used to measure
particles with a size range from 100 nm to
1000 um.
• It is based on sensing the electrical
difference caused when particles passed
through an orifice and displace some of the
electrolyte solutions in that orifice.
• The advantage of this method includes its
rapid, easy, accurate.
• The disadvantage is the size range limit
which cannot be used to measure smaller
particles.
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“Light Scattering”
1. Laser Diffraction:
• Light scattering techniques are the standard method in determining the particle size and
size distribution.
• When light is directed to the particle, it can either be deflected or absorbed by these
particles.
• Large particle diffracts the light and laser diffraction is used to measure the size of
larger particles such as pharmaceutical powders.
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“Light Scattering”
2. Dynamic Light Scattering (DLS)
• Small particles scatter the light in a different
direction.
• The detector is placed at a 90˚ angle or 175˚
angle (backscatter). This method is used to
measure the nano-sized particles. This
technique can detect particles from 1 nm –
~2 um.
• This method utilize the fact that the small
particles are moving with Brownian
motion.
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Mechanisms of Milling
1. Cutting:
• It involves the application of force over a very narrow area
of material using a sharp edge of a cutting device.
2. Compression:
• The material is gripped between the two surfaces and
crushed by the application of pressure.
3. Impact:
• Involves the contact of material with a fast-moving part
which imparts some of its kinetic energy to the material.
4. Attrition:
• The material is subjected to pressure as in compression, but
the surfaces are moving relative to each other, resulting in
shear forces that break the particles. 23
Milling Equipment
• Consists of:
• Feeder : to deliver the sample.
• Milling tools: act to reduce sample Mills
particle size.
• Discharge unit: to deliver the material
Cutting Impact
out of the mill. Compression Attrition
Cutter mill Pin
• Some mills contain a screen fitted in

Roller
Hammer Ball
Colloid Vibro-energy
the discharge unit which allows Edge and
End
Fluid-energy
particles under a certain size to pass

Spiral Jet
while the larger particle is returned to

the mill for further size reduction.
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Milling Equipment
1. Cutter Mill:
• A cutter mill consists of a series of knives
attached to a horizontal rotor which act
against a series of stationary knives attached
to the mill casing.
• During milling, size reduction occurs by
fracture of particles between the two sets of
knives, which have a clearance of a few
millimeters.
25
Milling Equipment
2. Roller Mill
• The same one was mentioned in lecture
one for mixing.
3. Hammer Mill:
• This one is rapid, convenient, and
inexpensive methods of producing fine
drug powders of about 10-50 µm.
• It is the most widely used milling
equipment in the pharmaceutical industry.
• https://youtu.be/fSTvbE77ucE
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Milling Equipment
4. Ball Mill
• This combines impaction and
attrition mechanisms.
• Ball mills consist of a hollow cylinder
mounted such that it can be rotated on
its horizontal longitudinal axis.
• The cylinder contains steel balls that
occupy 30–50% of the total volume.
• This type of mill is difficult to clean
and takes a long time for satisfactory
milling.
27
Mill Selection
Depends on:
1. Availability of the mill.
2. Product specification (size range, particle size
distribution moisture content, and physicochemical
properties of the material).
3. The capacity of the mill and production rate
requirements.
4. The versatility of operation (wet and dry milling)
5. Economical factor (cost, power consumption, space
occupied).
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Homogenization
• It is a technique used to mill a particle by processing a suspension of solid particles.
• It is originally used for emulsification (preparation for emulsion which is a dosage form
of two immiscible liquids).
• They are finding increasing application in the manufacturing of nanoparticles and
liposomes.
• It provides a mechanical force that causes droplet or particle size reduction by shear,
impact, and turbulence.
• Different homogenizers available such as:
1. Simple homogenizer.
2. Silverson homogenizer.
3. Ultrasonic homogenizer (laboratory scale).
4. Microfluidizer (high-pressure homogenizer).
5. Cyclone Homogenizer (low-pressure homogenizer). 29

MUCLecture 2022 3933148

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MUCLecture 2022 3933148

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Milling

• Higher mesh number means smaller opening diameter

• Some mills contain a screen fitted in

particles under a certain size to pass

while the larger particle is returned to

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