NANOPARTICLES IN PHARMACEUTICAL MANUFACTURING

The pharmaceutical field has long been a model for industry, creating best
practices in R&D, manufacturing, marketing and other disciplines. As such, it
also has recorded historic levels of profitability. But an evolving marketplace,
changing regulatory standards, increased manufacturing costs and a number of
other factors have begun exerting pressure on pharmaceutical producers. One of
the bright spots for the industry is nanoparticle technologies, which offers
seemingly unlimited potential to help solve health problems and thus grow the
pharmaceutical business.

Nanoparticles are loosely defined as substances with a product dimension of less

than 100 nanometers (nm, 0.1µm or 10-7m), but the category, particularly in the
area of pharmaceuticals, includes substances that are as large as 500 nm. For a
point of comparison, a human hair is approximately 80,000 nm wide.

First discovered by British botanist/surgeon Robert Brown in 1827, nanoparticles

find application in many states, including solid particles in suspension, powder,
dust, liquid drops in emulsion, fog, spray and foam.

Nanoparticles have four broad areas of By 2014, spending on

application in the combined
pharmaceutical/healthcare industry: nanoparticle research and
• Drug delivery
• Diagnostic products development is projected to
• Product packaging exceed $2.5 trillion annually.
• Biomarker discovery

In the discussion of nanoparticles, the dividing line between healthcare and

pharmaceuticals applications is often hard to distinguish. Diagnostic products, for
example, aren’t true pharmaceuticals in that they don’t directly affect change in
disease or illness. Yet those diagnostic products that employ nanoparticles are
typically researched and manufactured in processes similar to drugs; they are
delivered internally or applied to sick patients; and manufacturers operate under
many of the same rules and regulations. Products for biomarker discovery are
similar in these regards. Thus, they will be included in general terms in this white
paper.

The pharmaceutical industry already uses nanoparticles. They find use as carriers
in medicated topical creams and lotions, in what are called nanoemulsions, which
show better penetration and more even delivery compared to traditional emulsions.
Microfluidic systems transport nanoliter volumes of fluid for nucleic acid and
protein analysis, and micro-array platforms manipulate sub-nanogram quantities
of genetic materials in genomics and proteomics.1 Nanotechnology is also
currently working in cancer and anti-tumor medications.
Small is Big Business
Nanotechnologies are booming and will, by all accounts, continue to grow at
impressive rates. According to a Lux Research study reported in Small Times
(March 8, 2007), US$12.4 billion was spent on nanotech R&D worldwide in 2006.
More than $50 billion worth of nano-enabled products were sold globally that
same year. Projections by the U.S. National Science Foundation in 2004 estimate
spending to exceed $2.5 trillion annually by 2014.

The United States is currently the largest purveyor of nano research and products.
In 2001, the U.S. government launched the National Nanotechnology Initiative
(NNI), an interagency program that coordinates federal R&D efforts in this field.
The NNI projects its expenditures will exceed $1.4 billion in fiscal year 2008, an
increase of 212 percent since the program’s inception.

Within the all-encompassing category

of nanotechnology, the combined
healthcare products/pharmaceuticals
sector is generally estimated as the
second largest category by dollar value
(trailing electronics). Market
evaluations project that
nanobiotechnology will exceed $3
billion with an annual growth rate of 28
percent by 2008.2 In a 2007 study, the
Freedonia Group Inc., a Cleveland-based research firm, concluded that demand
for nanotech-based medical supplies and devices in the U.S. market will exceed
$110 billion by 2016. Additionally, nano-enabled products currently on the
market carry an 11 percent price premium compared to equivalent conventional
products.3

When the NNI was initiated, its charter listed 10 R&D targets to be addressed by
2015. Of those 10, five are relevant to drug development and delivery:
• No suffering and death from cancer when treated;
• Advanced materials and manufacturing;
• Pharmaceutical synthesis and delivery;
• Converging technologies form the nanoscale;
• Life-cycle biocompatible/sustainable development.

Nanostructure Classes and Development

The nanotechnology industry is still in its infancy, and the development of nano-
sized particles and structures has a long way to go. Particles for pharmaceutical
use are available in many different classes with advantages in various applications.
 Carbon fullerenes and nanotubes are made of carbon 60 atoms and have
numerous points of attachment. Nanotubes are among the most utilized
particles because they offer strength and excellent electrical properties.
The can be single-walled or multi-walled structures.

Ceramic nanoparticles are commonly derived from silica, titania and

alumina. The particles’ porous nature makes them suitable for drug
delivery, particularly in cancer treatment.

Emulsions are oil-in-water mixtures stabilized with surfactants. These

have been in use in the personal-care field for some time in anti-aging
creams and lotions.

Liposomes comprise lipid bilayer membranes around an aqueous interior.

The drug’s active compound can be positioned in the aqueous center if it
is water soluble or in the lipid layer if it is fat soluble.

Metallic particles include magnetic compounds, such as iron oxide, and

gold- and silver-coated particles. Magnetic compounds are being used for
targeting drugs. Gold-coated particles display excellent optical properties
needed for diagnostic imaging. Silver-coated particles show outstanding
anti-infection properties.

Polymers, including chitosan, and newer water-soluble hybrid polymers

are used in drug delivery. When attached to proteins, polymer
nanoparticles improve the protein’s stability and reduce antigen-incited
immune responses.

Quantum dots are fluorescent particles that are being researched for use in
tumor detection via spectroscopy, as well as other diagnostic applications.

In loose terms, there are four main groups of these structures, only two of which
have been realized to levels suitable for possible commercialization. At a Society
of Manufacturing Engineers conference in 2005, David Keenan characterized the
following groups.

Passive nanostructures are essentially individual particles that are

integrated into products to enhance the performance or characteristics of
other molecules. [These are already in widespread use in pharmaceutical
manufacture.]

Active nanostructures are building blocks that are manufactured to

specific shapes and sizes, with predetermined interfaces and positions.
[These component parts are currently used in many pharmaceutical R&D
projects. While a tiny number of active nanostructures may be
commercialized, most are still in clinical trials or still in research.
 Nanosystems combine passive and active nanostructures into simple
machines. Molecular nanosystems, the fourth phase of development, build
on nanosystems to create synthetic biology. Researchers have not yet
achieved these levels.

Pharmaceutical Applications and Advantages

As outlined above, the four major areas of research and development for
nanoparticles are product packaging, biomarker discovery, diagnostic products
and drug delivery.

Packaging
While critical to products and the overall pharmaceutical market, packaging is not
core to drug research and development, and is usually developed and
manufactured by companies other than the drug producers. As such, this is a topic
deserving of it own white paper. Thus, the section herein will be brief.

Polyvinyl Chloride (PVC) and Polyvinylidene Four major areas of

Chloride (PVDC) and its copolymers are
among the most common products that nanoparticle R&D
incorporate nanoparticles to improve
pharmaceutical packaging. PVC and PVDC
include drug delivery,
are commonly incorporated between diagnostic products,
cellophane, paper and plastics as a barrier to
gasses, odors and humidity that could foul the biomarker discovery
drug.
and packaging.
Manufacturers use nanoparticles as cross-
linking and reinforcement mechanisms in the polymer chains. This provides
physical strength at light weights. Nanotechnologies also improve packaging’s
optical properties, helping make it UV resistant and/or improving the clarity of
package windows.

Biomarker discovery
Biomarkers are molecules that can be measured in blood, body fluids and tissues
to assess the presence of disease or its state of development. Prostate-specific
antigen, or PSA, the indicator for prostate cancer, is perhaps the most widely
known biomarker in the general public. As early as 1998, nanoparticles were
being employed in successful in-vitro biomarker diagnostics for diseases such as
skin cancer.4 When used in proteomics and genomics technologies, nanoparticles
have been shown to help amplify biomarkers and protect them from degradation.
In 2006, the National Cancer Institute reported that researchers at the
Nanomaterials for Cancer Diagnostics and the Therapeutics Center for Cancer
Nanotechnology Excellence (CCNE) at Northwestern University developed an
ultra-sensitive method that can detect as few as 100 molecules of PSA in a drop of
blood that is six orders of magnitude higher sensitivity than conventional assays.

Similar results continue to be generated in many areas of biomarker research,

making this one of the brightest spots for nanomedicine.

Diagnostic Products
Like biomarkers, diagnostic imaging products find use in early disease detection.
They are also used to track disease metastasis and now, thanks to nanotechnology,
drug targeting and distribution. Nanoparticles are being used and tested to achieve
clarity, targeting and range previously unavailable in processes such as magnetic
resonance imaging (MRI), ultrasound, fluorescence and tomography.

Iron oxide particles are improving the effectiveness of MRI imaging.

Nanoemulsions using gadolinium complexes dramatically improve ultrasound
imaging.

Contrast agents bound to nanocarriers used for drug delivery are helping target
drugs to specific locations, such as tumors, and track the drug’s transmission
through the site. Such diagnostics help clinicians know when to administer the
next dose.
All common drug
Drug Delivery
Drug delivery represents what is potentially the delivery vehicles
largest immediate application for nanoparticles
can effectively use
in the pharmaceutical industry and perhaps the
widest area of use. There are more than 300 nanoparticles in
companies in the United States alone involved in
developing drug delivery mechanisms. their formulation.

According to the Pharmaceutical Research Manufacturers of America (PhRMA),

the average total cost to push a new drug through development in the United
States is more than $800 million. The process takes an average of 12 to 15 years,
leaving only five to eight years of U.S. patent protection. PhRMA further notes
that just one in 5,000 new compounds survives the process to become a new drug
in the marketplace.

An estimated 20 percent of those drugs that have made it to market since 1995 do
not perform up to their full potential because they have low bioavailability
(acceptance and uptake by the body). This can result in poor performance
characteristics, such as slow or variable onset, increased side effects and poor
compliance, as well as the need for higher dosing.
In addition to newly formulated drugs, nanoparticles can, in many cases, be
applied to reformulations to:
• improve the efficacy of current drugs that under perform;
• make viable many compounds that never made it through trial phase to
market;
• improve efficacy or limit side effects of older drugs now off the market or
off patent, allowing them to be re-introduced;
• change the method of drug delivery to improve customer acceptance or
reduce manufacturing costs.

All common delivery vehicles — oral, injection, transdermal, transmucosal,

ocular, pulmonary and implant — can effectively use nanoparticles in their
formulation. The technology offers numerous potential advantages that may apply
in some or all of these delivery forms. These advantages include, but are not
limited to, a number of functionalities depending on the drug’s specific
application and performance goals:
• prolong circulation in the blood;
• accumulate in the pathological area;
• enhance water or lipid solubility;
• respond to local stimuli, such as changes in pH, temperature or light;
• penetrate anatomical features such as cell walls, blood vessels, stomach
epithelium and blood-brain barrier; and
• selectively target specific cell types.

Numerous studies show that particles less than 100 µm in size have greater
absorption and delivery efficiency in the gastrointestinal, pulmonary and vascular
systems, and similar dermal penetration characteristics. This could prove
particularly beneficial to BCS class II, III and IV active pharmaceutical
ingredients, which typically have low solubility and/or low permeability. A drug
is considered to have low solubility at 0.1 mg/L. Industry analysts estimate that
about 10 percent of drugs currently on the market have poor solubility.

Nanodelivery has shown tremendous promise in targeting drugs at tumors. Tumor

microvasculature typically contains pores 100-1,000 nm in diameter, while
healthy heart, brain and lung tissue is 10 nm or less. So by manufacturing
nanoparticle-based drug molecules between 75-900 nm, researchers and
manufacturers have been able to create compounds that selectively target only
malignant tissue.

Recent research with the anti-cancer drug doxorubicin has shown it is more
effective on cancerous tumors when delivered via nanoparticle than through
traditional delivery mechanisms.
Nanotechnologies have also improved the reach of drugs, offering unique forms
capable of carrying RNA and DNA into subcellular structures to repair genetic
faults or to alter genetic expressions. Delivering proteins and peptides into cells,
an idea previously ineffective for a lack of delivery method, also shows great
promise in addressing diseases such as diabetes.

Research in the Journal of Physical Chemistry this year reported steps forward in
glaucoma treatment using nanoparticles. Only 1-3 percent of existing glaucoma
drugs delivered via liquid drops into the eye actually penetrate the eye, a very
poor rate of success. The nanodelivered treatments showed high penetration and
less abrasion.

Specific nanoparticle shapes can be used to encapsulate or bind drug compounds

to improve drugs’ solubility, stability or absorption rates. This allows
manufacturers to overcome numerous obstacles that have in the past been
research dead ends. In some cases, the problem has been tissue or cellular damage
or irritation associated with comparatively large doses of drugs. Nano-sized doses,
however, impart significantly less irritation or damage, which the body is able to
heal without adverse affect. Examples include drugs dosed via inhalers, which can
cause coughing and throat irritation.

Nanoparticle Creation by Media Milling

Media milling, commonly called grinding, is the most well documented and well
established method for creating small-scale particles, dating to the first half of the
twentieth century. The process of using force shearing to reduce the size of
particles into the nano scale has been
significantly improved during the last
quarter century and, when combined
with new dispersion techniques,
offers many benefits:

• excellent particle-size control

• comparative cost-
effectiveness
• equipment scalability, from
benchtop to production
• limited or zero contamination
of active Figure 1. NETZSCH Fine Particle
• repeatability of process Technology MicroCer media mill.
• meets cGMP production requirements
Popular because of their simplicity and scalability, fine bead mills also offer
lower costs compared to plasma gas and precipitation process techniques and
other alternative technologies. Often used in conjunction with plasma gas process
techniques, fine bead mills provide an efficient way to disperse the output to a
primary particle size, stable dispersion, assuming the proper stabilizing agents are
used (Figure 2).

The principle behind agitator bead mills is based on grinding of suspended solid
particles by impact and shearing forces between moving grinding beads. Kinetic
energy is transmitted to the grinding media by the agitator shaft within the stator
housing.

The achieved fineness is primarily defined by two basic parameters – the stress
intensity and the number of contact points. The stress intensity is a function of the
kinetic energy in the grinding beads. This energy must be high enough to produce
the grinding process. The number of contact points determines how often the
media interacts within the grinding chamber. A fine particle size distribution
requires a high number of contact points in the grinding chamber. To increase the
number of contact points, smaller grinding media must be used. The rule of thumb
is that particle size is equal to 1/1000 the size of the grinding media.

Figure 2. Particle Size Distribution with NETZSCH’s MiniZeta

Achieving Repeatable Nanoparticle Dispersions

Creating repeatable distributions of submicron particles is essential to using them
effectively in formulations. Traditional plasma gas processes promise superior
particle uniformity, but do not offer the ability to disperse particles in a solution at
their primary size. Precipitation processes produce large crystal sizes and
agglomerated, aggregated crystals in the range of 100 nm to 100 µm. A fine bead
mill with grinding media on the order of 100 µm to 200 µm is the simplest, most
scalable, most cost-efficient way to make and disperse nanoparticles.
But dispersing nanoparticles into liquids can be a challenging undertaking. The
tremendous surface area and surface energy which delivers the beneficial effects
of nanomaterials also prevents their easy dispersion into liquids. Intermolecular
forces increase as particles become smaller, causing cohesive forces
(agglomerates, aggregates or primary particles) in the product. Agglomerates are
formed by point-focal or linear cohesive primary particles, while aggregates form
by laminar binding. Primary particles are crystalline, or amorphous, particles that
are separated against each other. The goal is to disperse these particles to their
primary particle size. But conventional technologies for dispersing powders into
liquids are not sufficient for dispersing these tiny
particles as discrete entities. Mild dispersion
The production of stable suspensions or uses multiple mild
dispersions of nanoparticles requires a
communition process, such as a small-media mill
contacts instead of
provides. Mills using media beads in the range of one strong contact
70-125 µm can economically grind into the
nanometer range. to avoid breaking
Mill designs using ultra-fine grinding beads 70- and destruction.
125 µm in size offer an effective solution for
creating stable dispersions of these newly formed nanoparticles with outstanding
process efficiency as well. Called mild dispersion, this process uses multiple mild
contacts instead of one strong contact, which can cause breaking and destruction.

Many factors affect the function of mild dispersion, but the main principle is bead
size. Decreasing the diameter of the bead yields four primary results:
• The number of beads is increased dramatically.
• Contact of the beads with the product is increased dramatically.
• The weight of one bead is decreased dramatically (weight = diameter3)
(Figure 3).
• The energy of one bead is decreased dramatically (mean energy of one
bead is equal to the specific energy input divided by the number of
grinding beads).

Figure 3. Bead size to weight ratios

The smaller the bead size, the more beads there are per unit volume. For example,
if 1-mm beads are loaded into a 1-liter vessel, there are around 1.1 million beads.
But with 0.05-mm beads, there are 9.4 billion beads. So, the probability of
contacts between particles and beads increases significantly.

As the bead size decreases, the space between the beads decreases too, working as
a filtering mechanism that holds back large agglomerates and breaks them apart.
A rough calculation indicates the stand-off distance between the beads would be
44 µm for 1-mm beads and about 2 µm for 0.05-mm beads. Mild dispersion
provides a dynamic filtering mechanism holding back particles larger than the
standoff distance, and it shears them apart to their primary size. Together these
changes create uniformity and reduce particle damage while maintaining
productive work speeds.

Mill Choices
Selecting appropriate equipment is key to developing a repeatable process and
creating efficient workflow in the lab right through to full-scale production.

Obviously, the first requirement is that the equipment be appropriately sized for
the work and that it be scalable. New mills allow for the use of beads down to 100
µm in diameter while offering improved functionality that facilitates adequate
product throughput at slow, low-energy motor speeds (which prevents damage to
the nanoparticles) while providing practical methods for handling and removing
the fine grinding media at the end of the process.

The ideal mill would have “plug flow,” so

none of the batch is able to bypass the
grinding and all the material passes
through the machine at the same velocity,
producing a uniform grind and residence
time distribution; however due to the
turbulence in bead mills, this is not
possible, so rapid multiple-pass operations
are used to achieve a narrow particle size
distribution (Figure 4). Figure 4. Results of multiple-pass operation

Important for processing nanoproducts in agitator bead mills is the selection of

materials suitable for the grinding media and the grinding chamber to avoid
contamination of the products. Grinding zone parts manufactured completely with
Yttria Zirconia (YTZ), a high strength ceramic, offer metal- and contamination-
free grinding. Grinding beads are also available in materials such as plastics, glass,
ceramics like Al2O3 and ZrO2, steel and even tungsten carbide.
A Look Forward
As nanotechnology continues to evolve, so too will its application in
pharmacology and related biological health applications. Ongoing research points
toward nanotechnology’s benefits outweighing potential drawbacks in the
majority of applications in which it has been studied. Oncological uses seem to
hold early promise, but researchers have only scratched the surface. Nanoproducts
research across virtually all biomedical fields is yielding important strides forward.

There is no one nanotechnological solution, just as there is no one nanoparticle to

solve every application challenge. Matching technologies to challenges will
continue to demand intense research.

New nanoparticle production techniques and equipment will aid in furthering

discovery. Mild dispersion is a step in that direction, providing chemists and
researchers with a cost-effective method to disperse nanoparticles without damage
to the crystal structure.

NETZSCH Fine Particle Technology, LLC

125 Pickering Way
Exton, PA 19341
Phone: 484-879-2020
Fax: 610-280-1299
References
1. Mazzola, Laura, “Commercializing nanotechnology,” Nature Biotechnology,
Vol. 21, no. 10, Oct 2003.
2. Frontline Strategic Consulting, “Nanobiotechnology opportunities and
technical analysis,” 2003
3. Lux Research, Inc., “The Nanotech Report 4,” 2006.
4. M.K. Bhalgat, et al, “Green and red fluorescent nanospheres for the detection
of cell surface receptors by flow cytometry.” J Immunol Methods, 219: 57-68.

NETZSCH Fine Particle Technology, LLC

125 Pickering Way
Exton, PA 19341
Phone: 484-879-2020
Fax: 610-280-1299