Fred Surville, Jet Pulverizer
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.
Studies have linked micronization with the increased bioavailability of active pharmaceutical 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.
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. Basically, 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 application. Well-designed, high-speed mechanical mills can grind some friable materials to a low-micron size. Practically 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, however, 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. Ingredients can seriously erode hammermills, adding metallic contamination to the product. Bulk solids materials that degrade with heat or have low melting temperatures also are a problem for hammermills because the mills generate heat, typically reaching temperatures above 90°C (194°F). Materials such as active pharmaceutical 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 constant, 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, manufacturers previously had to mill the material, sieve out the oversized particles, and re-mill. The process was long, expensive, and inefficient.
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 micronization 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 temperature 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 bioavailability, 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 baseline, 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 manufacturing 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.
- McInnes, GT, et al. “Effect of micronization on the bioavailability and pharmacologic activity of spironolactone.” Journal of Clinical Pharmacology. 1982 Aug-Sep; 22(8-9):410-7.
- Chaumeil, JC. “Micronization: a method of improving the bioavailability of poorly soluble drugs.” Methods Find Exp Clin Pharmacol. 1998; 20(3): 211-5.
- 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.
- Pharmaceutical Technology editors. “Optimizing high-potency manufacturing.” Pharmatech, 2011; 35 (6); accessed on line 4/1/2018.
- 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
Fred Surville (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 technology sales and marketing skills on projects ranging from waste-to-energy, industrial zero-waste initiatives, 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
Copyright CSC Publishing Inc.