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Advantages of jet milling
 
Q: What are the advantages of jet milling?
 
 
Studies have linked micronization with the increased bioavailability of APIs 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; however, the studies typically include wet-milling techniques, which skew the findings.
 
Wet milling does tend to create finer particles but also increases costs and steps and adds many variables that dry milling doesn't include. In this article, I'll evaluate dry powder milling techniques and their effects on micronization, namely how mechanical, ball, and jet mills stack up against each other and why solid dosage manufacturers prefer jet mills.
 
Mill types
Mechanical mills. Hammer mills or pin mills are usually the first mills that solid dosage manufacturers consider when evaluating techniques for particle size reduction. Well-designed, high-speed mechanical mills can grind some friable materials to a low-micron size. Practically, a commercial hammer mill can obtain a particle size of 200 mesh (74 microns), with a typical mid-range particle size of 80 mesh (177 microns).
 
However, wear on equipment and product contamination is a serious problem when using a high-speed mechanical mill, as is attritional heat. Contamination is an issue in most material applications and can be very acute in pharmaceutical manufacturing, where ingredients can seriously erode most hammer mills, adding metallic contamination to the drug product. Materials that degrade with heat or have low melting temperatures are also a problem in hammer mills because the mills generate heat, typically reaching temperatures above 90°C. APIs and 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 R&D in the pharmaceutical industry. 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.
 
Apart from its comminution function, ball milling also serves as an intensive mixing technique capable of producing co-ground, drug-excipient mixtures comprising amorphous drug forms intimately 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 fine product, but the particle size distribution (PSD) tends to be very wide. By the time this type of mill reaches the correct average particle size, the number of fines is usually too high.
 
Mill suppliers can line ball mills with ceramics to reduce contamination from abrasive materials, but wear of the media is constant, which can contaminate a product.
 
Jet mills. Until the introduction of jet mills in 1936, dry grinding in the sub-sieve range of 625 mesh (20 microns) to 2,500 mesh (5 microns) was impractical. To create fine particles with a narrow PSD, previously manufacturers had to mill the material, sieve out the oversized particles, and re-mill. The process was long, expensive, and inefficient.
 
imageJet mills can mill materials to single-digit-micron particle sizes in a single pass, increasing yield and operational efficiencies (Figure 1). 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 wall of the milling chamber 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 surfaces of particles as they move rapidly against each other, resulting in shear forces that can break them up.
 
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 Joules Thompson 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 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. It also develops no attritional heat because of the cooling effect of the jets.
 
API bioavailability
imageOne 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 drug products (Figure 2)..
 
According to Charlie Johnson, head of the high-potency business at Carbogen Amcis, a contract manufacturing organization (CMO) of highly potent APIs, the increased emphasis on PSD affects high-potency manufacturing as well. He indicates that the increased specific surface area of finely ground APIs results in higher bioavailability, making particle-size control and distribution key parameters for solid dosage forms [4].
 
In his study of micronization processes for four drug products, 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 perfectly 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.
 
imageFinally, de-agglomeration and polishing of sharp edges is another great use of the jet mill (Figure 3). 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 APIs and excipients during formulation. Generally, both of these require a reduction in air pressure.
 
References
  1. McInnes GT, et al. Effect of micronization on the bioavailability and pharmacologic activity of spironolactone. J Clin Pharmacol. 1982 Aug-Sep; 22(8-9):410-7.
  2. Chaumeil JC. Micronization: a method of improving the bioavailability of poorly soluble drugs. Methods Find Exp Clin Pharmacol. 1998; 20(3): 211-5.
  3. 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 .
  4. Pharmaceutical Technology Editors. Optimizing high potency manufacturing. Pharmatech, 2011; 35 (6); accessed on line 4/1/2018.
  5. Kesisoglu F and Wu Y. Understanding the effect of API properties on bioavailability through absorption modeling. AAPS J. 2008 Dec; 10(4):516-525. Published online 2008 Nov 6. doi:10.1208/s12248-008-9061-4.

Fred Surville is vice-president of sales and marketing at The Jet Pulverizer Company. The Micron-Master Mills and Custom Grinding Division at the Jet Pulverizer Company provides equipment and particle size reduction services.

Do you have a question for our experts? Send your questions to pwright@cscpub.com, and we'll have an expert answer them.
April 23, 2018
 
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