As appeared in June 2020 PBE
Copyright CSC Publishing powderbulk.com
MICRONIZATION IN THE
PHARMACEUTICAL INDUSTRY
Micronization is the process of reducing a bulk solid material’s particle size to the micron or submicron level. This article
discusses dry powder milling techniques and their effectiveness for micronization, specifically in the pharmaceutical industry.
The article looks at how mechanical, ball, and jet mills stack up against each other.
S
tudies have linked micronization with the
increased bioavailability of active pharmaceu-
tical ingredients since the early 1980s.1 Simply
put, finer particles increase a material’s surface area,
which increases bioavailability, especially in poorly
soluble materials.2 Since then, considerable research
has evaluated the effects of different types of milling
on micronization. These studies, however, typically
include wet-milling techniques, which skew the
findings. While wet milling does tend to create finer
particles, it also increases costs and steps and adds
many variables that dry milling doesn’t include.
Mill types
Different types of mills have pros and cons when
trying to size-reduce material to the micron and
submicron level.
Mechanical mills. Hammermills or pin mills are
usually the first mills that pharmaceuticals, cosmetics,
or sanitary materials manufacturers consider when
evaluating techniques for particle size reduction. Basi-
cally, these mills have hammers or pins that rotate and
strike the material particles. The design, as well as the
number of pins or hammers, varies with the applica-
tion. Well-designed, high-speed mechanical mills can
grind some friable materials to a low-micron size. Prac-
tically speaking, a commercial hammermill can obtain
a particle size of 200 mesh (74 microns), with a typical
mid-range particle size of 80 mesh (177 microns).
Equipment wear and material contamination, how-
ever, are serious problems when using a high-speed
mechanical mill, as is attritional heat. Contamination
is an issue in most product applications and can be
very acute in pharmaceutical manufacturing. Ingredi-
ents can seriously erode hammermills, adding metallic
contamination to the product. Bulk solids materials
that degrade with heat or have low melting tempera-
tures also are a problem for hammermills because the
Fred Surville, Jet Pulverizer
mills generate heat, typically reaching temperatures
above 90°C (194°F). Materials such as active pharma-
ceutical ingredients and pharmaceutical excipients
that have lower melting temperatures or are prone to
heat degradation are usually not great candidates for
mechanical milling.
Ball mills. Ball mills tend to be the least expensive
and most obvious micronization option, especially
for pharmaceutical research and development. The
use of ball milling as a micronization technique for
enhancing drug solubility has been well supported by
literature as far back as the 1970s.
Ball mills micronize material by agitating it in a
vessel using steel or ceramic balls or other media.
Apart from ball milling’s comminution function, the
technique also serves as an intensive mixing technique
capable of producing co-ground, pharmaceutical-­
­excipient mixtures comprising amorphous drug forms
mixed with suitable hydrophilic excipients at the
molecular level.3
Milling is always a function of residence time in the
mill, but ball mills are especially sensitive to residence
time and can create long batch processes. Ball mills
equipped with a classifier can produce a finely sized
product, but the particle size distribution (PSD) tends
to be very wide. By the time this type of mill achieves
the correct average particle size, the number of fines is
usually too high (above 10 percent). Mill suppliers can
line ball mills with ceramics to reduce contamination
from abrasive materials, but mill media wear is con-
stant, which also can contaminate a product.
Jet mills. Until the introduction of jet mills in 1936,
dry grinding in the subsieve range of 625 mesh (20
microns) to 2,500 mesh (5 microns) was impractical. To
create fine particles with a narrow PSD, manufactur-
ers previously had to mill the material, sieve out the
oversized particles, and re-mill. The process was long,
expensive, and inefficient.
 Copyright CSC Publishing
FIGURE 1
Particle size distribution of ball-milled and jet-milled material
a. b.
1.000 10.00 100.0 1.000 10.00
Diameter (μm) Diameter (μm)
Jet mills can mill materials to single-digit micron
particle sizes in a single pass, increasing yield and
operational efficiencies, as shown in the graphs in
Figure 1. Figure 1a. shows ball-milled material’s PSD,
while 1b. shows a jet-milled material. In this microniza-
tion method, the mill injects high-velocity, compressed
air into a chamber where a rate-controlled feeder adds
the starting raw materials. As the particles enter the
airstream, they accelerate and collide with each other
and the milling chamber’s walls at high velocities.
Particle size reduction occurs through a combination of
impact and attrition. Impacts arise from the collisions
between the rapidly moving particles and between the
particles and the wall of the milling chamber. Attrition
occurs at particle surfaces as particles move rapidly
against each other, resulting in shear force that can
break up the particles.
In addition to creating fine particles with a narrow
PSD, jet mills have other qualitative advantages over
ball and mechanical mills. A jet mill cools the tempera-
ture of the air leaving the jets to about -200°F due to
the Joule-Thomson effect, and the product leaves the
mill no warmer than the air used for the grinding. The
heat generated by the friction from particle-to-particle
and particle-to-wall collisions is offset by the cooling
effect of the expanding air. This allows for dry milling
of a wider range of materials, especially more delicate,
heat-sensitive materials.
A jet mill allows the pharmaceutical manufacturer
to grind a friable or crystalline material to an average
particle size of 1 to 10 microns and to classify it in a
very narrow particle size range at the same time. The
mill has no moving parts to wear out or generate heat
and no screens to plug or be punctured. Jet mills also
develop no attritional heat because of the cooling effect
of the jets.
Active ingredient bioavailability
One of the most important characteristics of a jet-
milled product is the huge increase in surface area.
Milling a material that’s 30 mesh (595 microns) down
to 2,500 mesh (5 microns) results in 1,643,000 times the
number of particles and a surface area that’s 118 times
greater. This allows for faster chemical reaction times
and improved pharmaceutical ingredient performance.
The increased emphasis on PSD affects high-­
­potency manufacturing as well. For example, the
increased specific surface area of finely ground active
pharmaceutical ingredients results in higher bioavail-
ability, making particle-size control and distribution
key performance parameters.4
In one study of micronization processes for four
drug products, J.C. Chaumeil found that digestive
absorption of poorly soluble drugs depended on their
rate of dissolution and that decreasing the particle
size using fine-grinding mills, especially jet mills,
improved that rate.2 Using Chaumeil’s study as a base-
line, Muller et al. reported an increase of 50 percent in
the solubility of an insoluble antimicrobial compound
when the particle size was reduced from 2.4 μm to 800
or 300 nm.5
Applications beyond size reduction
One of the important secondary uses for jet mills is
blending powders. The operator can feed two or more
streams of material into a jet mill at the same time,
resulting in a homogeneous blend at the output. As
stated above, pharmaceutical manufacturers have long
used ball mills for blending while milling; however,
co-milling in jet-milling environments has delivered
consistent, homogeneous, and tighter PSD results.
Finally, de-agglomeration and polishing of sharp
edges is another jet mill use. The former application
applies generally to spray-dried or atomized materials,
which are very popular in the solid dosage manufac-
turing process, usually after wet milling. This step
usually creates a better-flowing product and further
increases surface area, improving bioavailability. The
latter application tends to interest R&D personnel in
pharmaceutical manufacturing for testing different
form factors of both active pharmaceutical ingredients
and excipients during formulation. Generally, both of
these require a reduction in air pressure.  PBE
References
1. McInnes, GT, et al. “Effect of micronization on the bioavail-
ability and pharmacologic activity of spironolactone.” Jour-
nal of Clinical Pharmacology. 1982 Aug-Sep; 22(8-9):410-7.
 Copyright CSC Publishing

2. Chaumeil, JC. “Micronization: a method of improving the

bioavailability of poorly soluble drugs.” Methods Find Exp
Clin Pharmacol. 1998; 20(3): 211-5.
3. Loh, ZH, Samanta, AK, Heng PWS. “Overview of milling
techniques for improving the solubility of poorly water-­
soluble drugs.” Asian Journal of Pharmaceutical Sciences.
2014; 10:255-74.
4. Pharmaceutical Technology editors. “Optimizing
high-­potency manufacturing.” Pharmatech, 2011; 35 (6);
accessed on line 4/1/2018.
5. Kesisoglu, F and Wu, Y. “Understanding the effect of API
properties on bioavailability through absorption modeling.”
AAPS J. 2008 Dec; b10(4):516-525. Published online 2008
Nov 6. doi:10.1208/s12248-008-9061-4.

For further reading

Find more information on this topic in articles listed
under “Size reduction” in Powder and Bulk Engineering’s
article index in the December 2019 issue or the article
archive on PBE’s website, www.powderbulk.com.

Fred Surville (fsurville@jetpul.com, 312-502-5818) is

vice president of sales and marketing for Jet Pulverizer.
After receiving his BA and MS in international affairs
from Florida State University, he developed his tech-
nology sales and marketing skills on projects ranging
from waste-to-energy, industrial zero-waste initia-
tives, and data center power and cooling. He recently
received his MBA from the University of Chicago Booth
School of Business.

Jet Pulverizer
Moorestown, NJ
800-670-9695
www.jetpul.com