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Jet milling in API manufacturing
 
Q: What role does jet milling have in active pharmaceutical ingredient (API) manufacturing?
 
 
imageSince the early 1980s, micronization has been linked to increased bioavailability of APIs [1]. Finer particles increase a material's surface area, which in turn increases bioavailability, especially in poorly soluble formulations [2]. Since then, considerable research has become available to evaluate different types of milling and their effects on micronization. This article focuses on jet milling: its uses, competitive advantages, and potential future uses for pharmaceutical production.
 
Particle size and API bioavailability
A primary reason for jet milling a material is to greatly increase its surface area. When you reduce a material's particle size from 30 mesh (595 microns) to 2,500 mesh (5 microns), the resulting material has 1,643,000 times more particles, and its surface area is 118 times greater. This allows for faster chemical reaction times, which means greater API bioavailability for pharmaceutical products.
 
Particle size reduction is a safe method of increasing an API's solubility without altering its chemical nature [3]. The Noyes-Whitney equation, developed in the late nineteenth century, describes how a decrease in a material's particle size and the corresponding increase in surface area increases the material's dissolution rate.
 
Chaumeil found that the dissolution rate of poorly soluble APIs determines the quality of their digestive absorption and that fine grinding, and particularly jet milling, such APIs to obtain smaller particle sizes can improve the dissolution rate [2]. Chaumeil's study examined dissolution for griseofulvin, progesterone, spironolactone, and diosmin and found that micronization improved their digestive absorption, and consequently, their bioavailability and clinical efficacy.
 
Using Chaumeil's study as a baseline, Muller et al., per CMS 10.43, reported a 50 percent increase in solubility for an insoluble antimicrobial compound when the particle size was reduced from 2.4 microns to 800 or 300 nanometers [4].
 
Jet mills
Until the introduction of jet mills in 1936, dry grinding in the subsieve mesh range of 625 (20 microns) to 2,500 (5 microns) was impractical. To create fine particles with a narrow particle-size distribution, manufacturers had to mill a raw material, sieve out oversized particles, and re-mill the powder. The process was long, expensive, and inefficient.
 
Jet mills can mill materials to single-digit microns in a single pass, increasing yield and operational efficiencies. These mills inject compressed air streams into a chamber where a rate-controlled feeder supplies 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 by a combination of impact and attrition from these collisions. Attrition occurs at particles' surfaces as they move rapidly against each other, resulting in shear forces that can break them up.
 
In addition to fine particle sizes and a narrow particle size distribution, jet mills provide 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 powder exits the mill no warmer than the air used for the grinding. Heat generated by friction from collisions and contact with the grinding chamber is offset by the cooling effect of the expanding air. This allows dry milling of a wider range of materials, and especially, of more delicate, heat-sensitive materials.
 
imageA jet mill allows the user to grind a friable or crystalline material to fine particle sizes—an average particle size of 1 to 10 microns—and simultaneously provide a very narrow particle-size distribution (Figure 1).
 
The mill has no moving parts to wear out or generate heat and no screens to plug or puncture. Also, it develops no attritional heat because of the jets' cooling effects.
 
Applications beyond size reduction
One important secondary use for jet mills is blending powders. An operator can feed two or more streams of material into the jet mill at the same time, resulting in a perfectly homogeneous blend at the output. Ball mills have long been used for blending while milling, but the advent of co-milling has delivered consistent, homogeneous blends with tighter particle-size distributions in jet-milling environments.
 
imageFinally, deagglomeration (Figure 2) and polishing of sharp edges is another great use for the jet mill. Deagglomeration applies generally to spray-dried or atomized materials, which are very common in solid dosage manufacturing, usually after wet milling. This step usually creates a better-flowing product and further increases surface area and bioavailability. Polishing tends to interest R&D manufacturers as they test different forms of both APIs and excipients in formulations. They use polishing to increase a material's flowability and improve tableting and capsule-filling operations. Generally, both processes require a reduction in pressure in the mill compared to micronization.
 
References
  1. McInnes GT, Asbury MJ, Ramsay LE, Shelton JR, Harrison IR. Effect of micronization on the bioavailability and pharmacologic activity of spironolactone. J Clin Pharmacol. 1982 Aug-Sep; 22(8-9):410-7. DOI: 10.1002/j.1552-4604.1982.tb02694.x.
  2. Chaumeil JC. Micronization: A method of improving the bioavailability of poorly soluble drugs. Methods Find Exp Clin Pharmacol. 1998 Apr; 20(3):211-5.
  3. Khadka P, et al. Pharmaceutical particle technologies: An approach to improve drug solubility, dissolution, and bioavailability. Asian Journal of Pharmaceutical Sciences. 2014 Dec; 9 (6):304-316. doi: 10.1016/j.ajps.2014.05.005.
  4. Muller RH, Peters K. Nanosuspensions for the formulation of poorly soluble drugs I. Preparation by a size-reduction technique. Int. J. Pharm. 1998;160:229-237. doi: 10.1016/S0378-5173(97)00311-6. doi: 10.1016/S0378-5173(97)00311-6.
 

 
Frederic Surville is vice president of sales and marketing at Jet Pulverizer, Moorestown, NJ. The company provides jet-milling equipment and particle size reduction services.
 
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July 6, 2020
 
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