The mechanical process of reducing the size of a material using high-energy systems is known as micronization. There are two major benefits from reducing the size of the particle in a pharmaceutical product: firstly, broader ranges of target sites are available; and secondly, smaller particle size results in an increase in the surface area and this facilitates improved clinical efficacy. The resultant particles are physically unstable with regions of induced disorder, otherwise known as amorphous material.
The process of reducing the size of convergent particles with two or more opposing currents was invented in 1881 when Frederic A. Luckenbach and John Wolfenden received their patent for an opposed fluid energy mill,1 but it was another 65 years before the first commercially-practical jet mills were introduced by The Jet Pulverizer Company. Prior to Luckenbach and Wolfenden’s invention, substances had been pulverised by grinding, stamping, or using powerful jets of air to project them against a metallic disk. However, there were disadvantages to this approach, such as powder contamination and mechanical wear and tear.
Modern micronization equipment still bears some resemblance to the equipment used back in the late 19th century. A jet mill, also known as a fluid energy mill, uses pressurized gas to produce high-energy particle-particle collisions within the jet mill grinding chamber. These high-energy collisions result in micrometer-sized particles or agglomerates of nanometer-sized single crystal primary particles.2 In some cases, they can also produce composite particles, which is where a host particle is coated with a second substance.
There are alternatives for producing small particles, such as spray drying, co-precipitation/crystal precipitation and particle homogenization, but none of these methods offer the same scalability as a jet mill. Furthermore, there are no moving parts within a jet mill and little heat associated with the milling process due to cooling effect of the jets, which is important in maintaining the stability of the active pharmaceutical ingredients (API).
Technical Challenges
The micronization of APIs presents a few technical challenges, in particular the inadvertent formation of amorphous regions of material at the site of particle-particle collisions.3 These regions are non-crystalline and lack the continuous structural order that is characteristic of a crystal. This presents a number of problems for formulators, and is especially problematic for inhaled API particles because the different properties found in amorphous regions can elicit a change in the aerosol deposition profile on storage. Amorphous regions often require additional processing to obtain a stable product prior to formulation. In extreme instances this can result in a micronized product that cannot be formulated using conventional manufacturing processes.
The extent to which the API forms amorphous regions depends on the material and the energy imparted during the micronization. Jet mills impart large amounts of energy to the milled material, leading to the production of proportionally more amorphous material. If the amorphous particles can be controlled and remain amorphous, this can be considered a controlled state, but in reality, this is very difficult to achieve. Amorphous materials are unstable and will attempt to revert to the more stable crystalline state. Water, in the form of moisture in the air, often facilitates this reversion.
Where amorphous surfaces are in contact with each other, the process of amorphous to crystalline reversion is particularly problematic. The abutting amorphous regions undergo simultaneous amorphous to crystalline reversion but this reversion bleeds into the neighboring particle causing the two particles to adhere to each other once they are crystalline. Since powders are rarely diffusely spread to the extent that neighboring particles are not in contact, when amorphous material is spread across an entire powder bed large agglomerates form in an unpredictable manner. Furthermore, upon reverting to the crystalline state, water is given up by the amorphous material thereby further facilitating this reversion.
Advanced Jet Milling
To avoid the formation of amorphous material, jet mill operators have tried to maximize the amount of water vapor in pressurized gas lines to achieve milling gas humidity in the region of 30 to 70% relative humidity (RH)4 while avoiding the production of a liquid condensate in the grinding chamber.5,6 These methods, however, require bespoke apparatus or costly modifications to supplement pressurized gas lines with moisture.
A recently developed technique that increases the capabilities of jet milling, introduces a liquid aerosol into the jet mill’s grinding chamber, thereby enabling the manufacture of a stable amorphous-free product without the need for additional time-consuming conditioning processes or costly manufacturing apparatus.
Introducing a liquid aerosol directly into the grinding chamber at the point of micronization avoids contaminating the pressurized gas lines leading to the jet mill grinding chamber. The liquid aerosol can be introduced under ambient temperature conditions that are less likely to denature delicate material, such as biologics. The use of a liquid aerosol also avoids the need to either heat the milling gas, or to modify or contaminate the pressurized gas feed lines. If required, the liquid aerosol can include one of, or a mixture of a pharmaceutically-active material, an additive and an excipient depending on the formulator’s requirements. This now expands the capability to manufacture a greater range of morphologically different products in a jet mill including, for example, API combinations in a single particle.
Case Study: Jet Milling with Liquid Aerosol
A study was carried out to demonstrate that adequate moisture levels in the presence of high velocity collisions assist with the reversion of the surface amorphous regions back to crystalline material, thereby obtaining a thermodynamically stable particulate product.
Glycopyrrolate (a quaternary ammonium compound) was chosen as a model API because it readily demonstrates physical instability when micronized under dry conditions, and has a known susceptibility to produce amorphous material during comminution.7
This instability is demonstrated when the amorphous regions between neighboring particles revert to their crystalline form, resulting in inter-particle bridging, rendering the material unsuitable for use in an inhalation product.
A controllable ultrasonic water nebulizer was positioned across the venturi of a spiral jet mill to introduce liquid aerosol at the site of comminution. The output gas humidity was measured using a portable hygrometer inserted into the exit port of the jet mill and recorded throughout each processing run.
As a control, glycopyrrolate was micronized using dry micronization conditions (formulation A), whereas the test material was micronized in the presence of liquid aerosol (formulation B). The micronization was performed using compressed air with an inlet pressure of 5 Bar, a grinding pressure of 3 Bar and an average feed rate of 2 g/min delivered via a vibratory feeder.
The particle size distributions were determined by both wet and dry laser diffraction analysis methods and the amorphous content was assessed by dynamic vapor sorption (DVS), immediately following the micronization step.
Dry analysis involved using a laser diffraction particle size analyzer, equipped with the dry dispersion method at 4 Bar. Wet analysis used the laser diffraction particle size analyzer equipped with the wet dispersion unit, filled with iso-octane (2,2,4-trimethylpentane). This pre-dispersion was sonicated for three minutes using a sonic probe at 50% intensity. The optical properties for both methods used a refractive index of 1.52 and an absorption value of 1.0.
DVS was carried out using an automated multi-vapor gravimetric sorption analyzer. The humidity was increased from 0–90% RH then returned to 0%, both in steps of 10% RH. The DVS methodology required a mass change of 0.001% dm/dt before moving on to the next step. A time-out limitation was imposed in the event the threshold was not met within the predetermined period of six hours. In addition, samples were stored for 24 hours and then photographed to illustrate the re-crystallisation.
The effects of uncontrolled re-crystallization are illustrated in Figure 1. Initially, both samples contained a level bed of micronized glycopyrrolate (indicated by black line on each scintillation vial), but over 24 hours, Formulation A contracted in both the horizontal and vertical planes resulting in a frustoconical cone and turned into a solid mass. However, Formulation B remained as discrete particles with no change in bulk volume.
The particle size analysis results (see Table 1) demonstrate the change in particle size distribution resulting from the re-crystallization. There is a clear increase in measured particle size, which is believed to be due to the agglomeration of primary particles.
The wet laser diffraction analysis method employed a sonication process that is capable of breaking the agglomerates into their primary particles; the dry laser diffraction analysis method did not use a sonication process but instead used a 4 Bar dispersion pressure which is incapable of breaking these agglomerates.
Under ambient conditions, this agglomeration started immediately following micronization. In contrast, when the liquid aerosol was used in the process, the size of the resultant particles remained stable, confirming the visual observation shown in Figure 1.
This stability is believed to result because particle micronization in the presence of liquid aerosol creates an environment for the amorphous material to quickly convert back to the crystallized form before these particles have an opportunity to agglomerate.
The DVS traces (Figures 2 and 3) show the presence of amorphous material in the two formulations.
Conclusion
Adequate moisture levels in the presence of high velocity collisions assist with the reversion of the surface amorphous regions back to crystalline material, thereby obtaining a thermodynamically stable particulate product. Contrary to conventional thinking, the results of this study demonstrate that when liquid aerosol is introduced into the grinding chamber of a jet mill it does not create a slurry. Instead, the liquid aerosol confers important benefits without the need for time-consuming conditioning processes or costly manufacturing apparatus.
References
- United States Patent Number 238,044
- Chauruka SR, Hassanpour A, Brydson R, Roberts KJ, Ghadiri M, Stitt H: Effect of mill type on the size reduction and phase transformation of gamma alumina. Chem. Eng. Sci. 2015, 134: 774–783.
- Ward GH, Shultz RK: Process induced crystallinity changes in albuterol sulfate and its effects on powder physical stability. Pharm Res. May 1995, 12(5): 773–9.
- Chan H, Kwok P: Novel particle production technologies for inhalation products. In Inhalation Drug Delivery: Techniques and Products. Edited by Colombo P, Traini D, Buttini F. John Wiley & Sons, Ltd, 2013, 47–62.
- Vemuri NM, Brown AB, Authelin J, Hosek P: Milling process for the production of finely milled medicinal substances. International patent application number PCT/GB99/04041, December 1999.
- Hatton, AG: fluid energy milling process and apparatus, International Patent Application numbers PCT/GB1999/001189, October 1999.
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