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22 / June 2020 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. 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. 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