Crystallization involves several main steps: supersaturation, nucleation, and crystal growth. Both nucleation and crystal growth depend on the level of supersaturation. Industrial crystallization usually takes place within chemical reactors, which can be scaled up for large-batch production. Since it is not easy to achieve a uniform supersaturation level inside the reactor, conventional crystallization suffers from disparity in the rate of nucleation and the subsequent crystal growth. This will lead to poor control over the particle shape and size distribution. In general, this process tends to produce crystals >10 μm, with a broad size distribution, which will not be suitable for inhalation to the lungs.

After crystallization, the precipitate is collected by filtration and is dried in an oven at a set temperature. To reduce the particle size of the crystals, milling (e.g. fluid-energy/air-jet-milling or ball milling) is commonly employed in the pharmaceutical industry. In ball milling, powder contained inside a drum is grounded by rolling balls of various sizes as the drum rotates. In fluid-energy milling, compressed air is fed along with the powder into the mill, where the air accelerates and causes attrition of the particles by collision. Due to the high energy imparted to the particles in the milling process, they become partially amorphous, with reduced crystallinity (and hence attain a higher energy state than the fully crystalline materials). These particles can also carry electrostatic charge, resulting from friction or contact with the mill surface—a process known as trioboelectrification. Having higher surface energy and charge, these particles are very cohesive, making the powder difficult to handle. Furthermore, the powder will recrystallize from the partially amorphous state under elevated temperature and humidity conditions, causing potential instability problems during manufacturing and storage. An additional problem is that malleable materials such as inhaled steroid drugs (e.g. triamcinolone acetonide) are difficult to mill [1]. Despite these limitations, crystallization and milling are established techniques and have been widely used in the past for inhalation products [2–4].

However, because of the potential limitations of the conventional production process, alternative methods have emerged for the manufacture of powders with enhanced performance, increasing the amount of fine particles in the aerosol—with less device retention—and reducing dose variability.

Micronization may produce partially amorphous materials with a surface charge, causing particle agglomeration. These problems can be dealt with by specialized milling methods.

4.3.1 Fluid-Energy Milling at Elevated Humidity

In order to reduce the amorphous content in the material produced by milling, the milling can be carried out at elevated humidity. The absorbed moisture functions as a plasticizer to lower the glass transition temperature of the amorphous material, hence facilitating in situ crystallization during the milling process. The milled products have been reported to be predominantly crystalline, with particle size distributions similar to those produced by the conventional milling process [5]. The setup involves controlling the relative humidity (e.g. 30–70%) of the milling chamber by humidifying the feed gas (e.g. by superheated steam, to minimize condensation) used to mill the powder [5].

4.3.2 Wet-Milling Nanotechnology

Nanocrystal Technology (Elan Drug Technologies, King of Prussia, PA, USA) is an aqueous-based milling process used to reduce particle size to below 400 nm. A conventional ball mill can be used for the process, and the materials selected for the grinding media (e.g. glass, zirconium oxide) have been reported not to be crucial [6]. However, the grinding media should preferably be ≤1 mm in order to be effective in attrition and to impart less wear to the mill [6]. Milling in a water medium causes amorphous-to-crystalline transformation, and the resulting powder is physically more stable than that produced by dry milling.

Budesonide and other compounds were milled to nanosized particles, which were then spray- or freeze-dried for use in MDI, DPI, or nebulizer systems [7, 8]. A surface modifier (e.g. PVP, lecithin, cellulose derivatives) is usually added during or after milling to prevent agglomeration of the nanoparticles. Although these stabilizers can be of generally-recognized-as-safe (GRAS) materials, long-term inhalation can be a concern unless proven safe. Another major drawback of wet milling is that, depending on the type of mill and the drug, a lengthy processing time may be required (5 days or longer).

Another process used for wet milling is high-pressure (piston-gap) homogenization, which uses cavitation forces and impact or shear forces to reduce particle size. In this technique, the drug powder to be milled is dispersed in an aqueous solution containing a surface modifier (surfactant or polymer) and then stirred at high speed to form a suspension. It is then milled in a piston-gap homogenizer to <5 μm. This method has been used to produce budesonide nanosuspension containing drug particles of 500–600 nm suitable for nebulization [9]. In addition to the requirement for preprocessing the powder into a suspension, low suspension viscosity (hence low solid loading of <10%) may be a limitation of this method.

Inhalable particles can potentially be obtained by rapid precipitation from aqueous solutions using antisolvents. A number of processes have emerged to control the nucleation rate and crystal growth, so as to reproducibly generate particle size in the micron range for aerosol delivery.

4.4.1 Sono-Crystallization