Creating nanoparticles via media milling for drug delivery applications
By Harry Way
Technical Director
NETZSCH Fine Particle Technology
Industry estimates from 2006 put the cost of drug development at more than $1.2 billion. That number is probably well over $2 billion when the cost of failed prospect drugs is factored in. With costs skyrocketing, margins slipping and containment efforts being launched much faster than new drugs, it may surprise you that the biggest wave in drug-delivery research is small - nano-sized, actually.

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Nanoparticles may be the industry's best chance to organically (that is, without artificial actions, such as outsourcing to emerging nations) reduce costs, by improving the rate of development successes. Nanotechnologies have application across all industry sectors and new innovations continue to expand applications, creating a ripple affect on drug delivery possibilities.

Nanotechnologies are booming and will, by all accounts, continue to grow at impressive rates. According to a Lux Research study, 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.

Within the broad category of nanotechnology, the combined healthcare products/pharmaceuticals sector is estimated as the second largest category by dollar value. Market valuations put nanobiotechnology at more than $3 billion with an annual growth rate of 28 percent by the end of this year. The Freedonia Group Inc., a Cleveland-based research firm, concluded in 2007 that demand for nanotech-based medical supplies and devices in the U.S. market will exceed $110 billion by 2016.

Of all the possible drug applications for nanotechnology, drug delivery is currently the most developed and seems to be the most promising for improving drug effectiveness and commercialization for the long-term. Currently, more than 300 companies in the United States alone are involved in developing drug delivery mechanisms using nanotechnology.
Applications and Advantages

Drug development averages 12 to 15 years and just one in 5,000 new compounds makes it to the consumer market. Thus, pharmaceutical companies are searching for ways to improve the odds.

There are countless reasons why compounds don't make it past the trial stage, including:
  • poor bioavailability
  • poor solubility
  • insufficient shelf life
  • insufficient half life
  • strong side effects
  • poor targeting
These 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.

Nanoparticles can theoretically improve all common drug administration techniques - oral, injection, transdermal, transmucosal, ocular, pulmonary and implant.

Numerous studies show that particles less than 100 nanometers (nm) 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 III and IV active pharmaceutical ingredients, which typically have low solubility (less than 0.1 mg/L) and/or low permeability.

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. Examples include drugs dosed via inhalers, which can cause coughing and throat irritation. Nano-sized doses, however, impart significantly less irritation or damage, which the body is able to heal without adverse affect.

Additionally, nanotechnologies may allow producers to shorten the production cycle and save money by revisiting and reformulating compounds that never made it through trial phase, as well as older drugs now off the market or off patent, allowing them to be re-introduced. Companies can also change the method of drug delivery to improve customer acceptance or reduce manufacturing costs.
Nanoparticle Creation by Media Milling

Media milling, commonly called grinding, uses force shearing to reduce particles into the nano scale. When combined with new dispersion techniques, NanoGrinding offers many benefits
  • excellent particle size control
  • comparative cost effectiveness
  • equipment scalability, from benchtop to production
  • Limited or zero contamination of active
  • Repeatability of process
  • 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, as well as other alternative technologies. Fine-bead mills provide an efficient way to disperse the output in primary particle size assuming the proper stabilizing agents are used.

In bead milling, kinetic energy is transmitted to the grinding media by the agitator shaft in the stator housing. Particle fineness is primarily defined by two basic parameters: the stress intensity and the number of contact points. Stress intensity is a function of the kinetic energy in the grinding beads. The number of contact points determines how often the media interacts in the grinding chamber. Fine-particle distribution requires a high number of contact points, achieved by using smaller grinding media in the range of 50-200 µm. The rule of thumb is that particle size is equal to 1/1000 the size of the grinding media.

Achieving Repeatable Nanoparticle Dispersions Creating repeatable distributions of submicron particles is essential to using them effectively. Traditional plasma gas processes deliver superior particle uniformity, but do not offer the ability to disperse particles in a solution at their primary size. That's because 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 as discrete entities. Creating stable suspensions or dispersions of nanoparticles requires a communition process, such as a small-media mill provides.

Using 75- to 125-µm grinding beads produces multiple mild contacts instead of one strong contact, which can cause particle breaking and destruction. This mild dispersion yields excellent product with outstanding process efficiency.

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).
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).

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. A rough calculation indicates the stand-off distance between the beads would be 44 µm for 1 mm beads and 2 µm for 0.05 mm beads. Mild dispersion holds back particle agglomerates larger than the standoff distance, shearing them apart to their primary size. These changes create uniformity and reduce particle damage while maintaining productive work speeds.
Mill Choices

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

New mills offer adequate product throughput at low-energy motor speeds, which prevents nanoparticle damage, while providing practical methods for handling and removing the grinding media at the end of the process.

The ideal mill will have "plug flow," so no product bypasses the grinding. Plug flow also ensures that all of the product passes through the machine at the same velocity, producing a uniform grind and residence time distribution.

Selecting appropriate materials of construction for the grinding media and mill chamber is also critical. The right material will prevent unwanted reactions and transfer contamination, which waste time, money and materials. This last point is particularly important in lab-sized batched where there may be a limited inventory of target compound available for testing.

Grinding-zone parts manufactured completely with yttria zirconia (YTZ), a high strength ceramic, allow for processing that's free of metal contact. Grinding beads are also available in materials such as plastics, glass, ceramics (including Al2O3 and ZrO2), steel and even tungsten carbide.

With the right media milling equipment, researchers can cost-effectively create nanoparticles for drug delivery that are uniform and readily available. Nanotechnology offers hope for commercial development of new drugs, as well as the reintroduction of older drugs that are off the market or off patent. They can also improve the efficacy of current formulations. These advantages will help reduce the time and cost of product development while improving drug performance and patient outcomes.
About the author:

Harry Way has worked with NETZSCH Fine Particle Technology, LLC, for 23 years as a field service engineer, laboratory manager, manager of research and development, and currently as technical director.

Way has published 15 articles and regularly presents seminars on the grinding and dispersion process at conferences and customer sites. In addition to his responsibilities for application engineering, he is in charge of the marketing efforts for NETZSCH in North America.

Way attended the University of Pittsburgh and received his degree in Mechanical Engineering from Delaware Technical College.

Way is a member of the American Ceramics Society (ACerS), American Chemical Society (ACS), The Retail Confectioners Institute (RCI), and the Federation of Societies for Coatings Technology (FSCT): NETZSCH's MicroCer, with YTZ grinding zone parts, handles 75 - 80 ml batches with 0.05 to 0.8 mm grinding media to produce consistent particle reductions down to 200 nm. This equipment is scalable up to full-production.