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Emphasis on Innovation: Precision Particle ReductionEnables New Drug Delivery Methods

Wed, 11/02/2005 - 6:50am
With the ability to reduce drugs to sub-micron particles of uniform size, exciting drug therapies and delivery methods are emerging. In fact, precision particle reduction processes are becoming as essential to 21st century medicine as the mortar and pestle were for the 19th century pharmacy.
AT A GLANCE
•Drug delivery devices

•Key equipment attributes

•Homogenization

By Chris Werner

The M-110EH is an electric-hydraulic laboratory processor for high shear fluid processing. With constant process pressures ranging from 2,500 to 25,000 psi, it maximizes the energy-per-unit fluid volume, resulting in uniform submicron particle and droplet sizes.
When it comes to the latest drug delivery methods, size does matter. Pharmaceutical and biotechnology companies are utilizing processes that reduce medications to sub-micron particle sizes in order to better control the timing and location of a drug’s release in the body. New delivery methods improve the efficacy of treatments and also increase safety by minimizing or eliminating contact with parts of the body that could be irritated or harmed. Reduction of particle size to the nanometer scale enhances mature drug delivery methods and enables innovative approaches.

For example, new kinds of drugs can be administered—drugs that previously could not be absorbed through the digestive tract and could not be administered through injection without risking the blockage of blood vessels. Through precision particle reduction, it is now possible to inject aqueous solutions containing tiny bits of drugs, nutrients, or DNA that have been encapsulated in liposomes consistently smaller than the diameter of the capillaries in the human body—all but eliminating the risk of thrombosis.

The efficacy of oral medications also can be enhanced because the reduction of particles to sub-micron size and the attendant change in surface morphology can improve solubility and enable the body to metabolize substances that would otherwise be excreted. In fact, precision particle reduction technology is critical to the efficacy and safety of a wide variety of many drug delivery methods, not only intravenous and oral delivery, but also inhalers, topical ointments, transdermal patches, and implanted devices.
Equipment Requirements
Formulators of new drugs and developers of new delivery methods require particle reduction equipment with the following key attributes.

1. Small particle size The process must be capable of reducing particle size to the desired sub-micron dimensions.

2. Uniformity of size The product must have a narrow particle size distribution. In other words, the range of size must be limited. Usually, efficacy and safety issues dictate an upper limit in size. Occasionally, a minimum size threshold is also specified. For example, if the particles in a topical treatment are too small, they could migrate through the skin and into the blood stream and cause harm to the patient. Similarly, for inhaled pharmaceuticals, if the particles are too small, they will pass into parts of the lung where they are not efficacious.

3. Controlled force During the particle reduction process, the amount of force applied should be precisely controlled to ensure that the desired results are achieved without over-processing any portion of the product. The controlled and uniform application of force ensures that the correct surface morphology is achieved and that valuable material is not destroyed during cell disruption processes.

4. Scalability Once the process is refined and proven in the laboratory, it should be possible to design and build pilot- and production-scale systems that produce the identical product at a predictable flow rate.

Types of Homogenizers

Three types of homogenizers are commonly used for particle size reduction in the pharmaceutical and biotechnology industries: conventional homogenizers, sonicators, and high shear fluid processors. They are described below.


A lab technician operates a custom-designed, computer-controlled processor.
1. Conventional homogenizers The conventional homogenization process was originally designed for processing milk and other dairy products. Auguste Gaulin received a patent in 1899 for a milk homogenization mechanism that reduced the size of fat globules in order to prevent the formation of a cream layer. It is a mechanical process which forces milk under high pressure through a tiny orifice. Over the past century, more than 100 additional patents have been awarded for improvements on Gaulin’s original design to produce smaller average particle size and achieve higher levels of precision than traditionally required by the dairy industry. For advanced products, conventional homogenizers can be designed to perform a variety of cell disruption, particle size reduction, and emulsification operations by selecting or creating a particular orifice size and valve geometry and by adjusting the pressure.

However, for conventional homogenizers, the orifice size, valve geometry, and pressure settings apply only to a specific flow rate. When scaling up from a laboratory-size homogenizer to a pilot system and when scaling up from a pilot system to a full-scale production system, completely different valves are used and the pressure may need to be raised or lowered considerably. Sometimes several iterations of equipment design must be tested before an acceptable product is produced or until the specified flow rate is achieved.

Although conventional homogenization has served the needs of the dairy industry for over a century, particle reduction applications in the pharmaceutical and biotechnology industries require a level of precision, uniformity, and predictability that are usually best achieved with newer homogenization technology.

2. Sonicators Sonic disruptors, or sonicators, break up particles in liquid media with powerful ultrasonic waves ranging from about 15 to 50 kHz. Ultrasonic waves in these frequencies are inaudible to the human ear but are capable of exerting pressures of more than 500 atmospheres and generating temperatures of up to 5,000°C. A probe or horn containing a piezoelectric generator amplifies the waves into an intense beam that creates the cutting or shearing effect on particles. This effect is called cavitation. At a microscopic level, the pressure waves cause bubbles to form and then grow and collapse violently. This implosion generates a shock wave that reduces particle size. The process is so powerful that it can easily over-process materials, excessively pulverizing the product. Sonicators are commonly found in the laboratory, but they can be prohibitively expensive for producing commercial production volumes.

3. High shear fluid processors A relatively new method of particle reduction is high shear fluid processing. It is favored by many research laboratories and pharmaceutical and biotechnology companies because of its unparalleled ability to produce extremely small particles of uniform size.

High shear fluid processing systems contain an electric-hydraulic system providing power to one or two single-acting intensifier pumps. The pump amplifies the hydraulic pressure to the selected level, which imparts that pressure to the product stream. Process pressures range from 2,500 to 40,000 psi, resulting in high-velocity high shear process streams. The intensifier pump supplies the desired pressure at a constant rate to the product stream. As the pump travels through its pressure stroke, it drives the product through precisely defined fixed-geometry microchannels within the interaction chamber. At the end of the power stroke, the intensifier pump reverses direction, and the new volume of product is drawn in. The intensifier pump again reverses direction and pressurizes the new volume of product, repeating the process. As a result, the product stream accelerates to high velocities, creating shear rates within the product stream that are orders of magnitude greater than any other conventional means.

All of the product experiences identical processing conditions, producing uniform particle and droplet size reduction. The fixed geometry of the microchannels not only ensures that the processing conditions are identical for all product passing through a single machine, but the processing conditions are also identical for all machines using a particular interaction chamber design and pressure setting, regardless of flow rate capacity. Therefore, once a high shear fluid processor achieves a successful result with a small laboratory system producing only a few hundred milliliters per minute, then the same interaction chamber and pressure specifications can be used in the design of a full-scale production system that produces significantly higher flow rates. Because of the ability to scale up production seamlessly, many users of high shear fluid processors skip the usual pilot stage and move directly from the laboratory to full-scale commercial production capacity.

Chris Werner is the vice president of engineering at Microfluidics, 30 Ossipee Rd., Newton, MA 02464. He has more than 20 years of experience with laboratory automation products and services. Microfluidics is a wholly owned subsidiary of MFIC Corp. and provides patented high-performance materials processing equipment. Werner can be reached at 800-370-5452 or cwerner@mfics.com.

ONLINE
For additional information on the technologies discussed in this article, see Medical Design Technology online at www.mdtmag.com or Microfluidics at www.microfluidicscorp.com.
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