Productivity and flow rate
Particle size can be fine-tuned by varying the feed-solution flow rate. The particle size can be decreased by slowing down
the feed-solution flow rate at a given solute concentration. Similarly, the particle size can increased by speeding up the
feed-solution flow rate. Although the particle size can be tuned by adjusting the feed-solution rate, the corresponding gas
pressure has a significant effect on the resulting particles (see Figure 5). This feature is important in using SAX for morphology
Figure 5 (ALL IMAGES ARE COURTESY OF PROSONIX.)
Temperature plays a major role in the SAX technology. It mainly influences the evaporation rate of the solvent employed in
the process. Ultimately, it governs the particle size of the drug. Although particle size is the key parameter affected by
temperature, thermal effects can influence the amorphous or crystalline character of the particle. This idea is of paramount
importance when nonsolvent temperature is selected.
Ultrasound and nonsolvent
Power ultrasound and the selection of the appropriate nonsolvent are the keys to collecting concentrated droplets and inducing
ultrasound-assisted nucleation. Applying ultrasound delivers astonishing results in terms of particle shape (see Figure 6).
However, the choice of solvent has an equal effect on the resulting particles. SAX technology in general has shown potential
in morphology control. It helps to generate the targeted particles and engineer them to the requirements of their ultimate
Figure 6 (ALL IMAGES ARE COURTESY OF PROSONIX.)
Useful scale-up equipment for ultrasonic processing has become available during the past 15 years. Probe-based systems generally
have inherent problems associated with cavitational damage and inefficient power consumption. Adapting such systems for the
pharmaceutical industry is difficult because they must be approved for use with flammable solvents—an essential feature of
equipment for manufacturing fine chemicals and APIs.
Prosonix has designed its piezoelectric-based Prosonitron equipment to allow focused distribution of acoustic energy into
a liquid by using several low-power transducers (21 in a 5-L flow cell) bonded to the outside of a cylindrical duct, as shown
in Figure 1, (7, 8, 23). A new cells with one row of seven transducers, (see Figure 2) was designed specifically for kilo-laboratory
and pilot-plant use, either in recirculation or continuous mode.
The key feature of the Prosonitron design is that the most significant transient cavitation takes place in the center of the
device. The equipment is modular and easily cleaned for production according to current good manufacturing practice. It also
can be steam-sterilized and is therefore useful for the aseptic manufacture of antibiotics, for example.
For manufacturing operations, it is more usual to configure a small ultrasonic flow cell into a recirculation loop, as shown
in Figures 1 and 2, with a larger and existing reactor, crystallizer, bioreactor, or fermenter.
It seems more sensible to use this retrofit option and to be able to wheel the ultrasonic module from vessel to vessel or
plant to plant than to build larger ultrasonic reactors. This configuration can also be modified easily to incorporate a secondary
feed stream of solute solution or antisolvent directly into the intense ultrasonic field. For techniques such as SAX, the
Prosonitron is a key element in large-scale production equipment (see the left of Figure 3).