Dispersions, sonocrystallization, and DISCUS
Antisolvent precipitation is an indispensable tool for the process chemist. Crystallization can often be achieved by mixing
a solution of the drug substance with an antisolvent so that, after mixing, the solution is supersaturated and crystallization
occurs. The extremes of supersaturation usually cause precipitation of amorphous and ultrafine particles.
Figure 1 (ALL IMAGES ARE COURTESY OF PROSONIX.)
One can take advantage of these effects by mixing in the presence of an ultrasonic field. The two streams can be mixed either
in continuous mode, using Prosonix's SonoLab ultrasonic devices, or in a recirculation process loop (see Figures 1 and 2).
In the latter, the antisolvent stream is recirculated rapidly through the flow cell while the optional feed API solution is
fed slowly into the flow cell (see Figure 2). Flow-rate ratios in this process often exceed 100:1 in favor of the recirculating
antisolvent. High flow rates lead to rapid dispersion and crystallization of micrometer- and submicrometer-sized particles,
which can then be isolated by spray drying, for example. Chemists would most often add antisolvent (e.g., the optional feed
in Figure 2) to the API solution, but this reverse-antisolvent process is essential to avoid the particle growth that occurs
during a normal antisolvent process. Prosonix's DISCUS is a dispersive technology that uses ultrasound.
Figure 2 (ALL IMAGES ARE COURTESY OF PROSONIX.)
Prosonix has produced several microcrystalline steroids using this reverse process, which is an effective means of preparing
mesoscopic crystalline particles at industrial scale. The reverse process provides many options. For example, the nonsolvent–solvent
system may be miscible (e.g., an ethanol solution dispersed into heptane) or immiscible (e.g., dichloromethane or toluene
dispersed into water). Volatile solvents or solvent azeotropes can be continuously removed. One can also feed a melt of the
API (provided its melting point is not exceptionally high) into the recirculating antisolvent. All these methods can be used
for preparing aqueous nanosuspenions, often with the use of stabilizers.
Ultrasound-mediated emulsion crystallization is a novel particle-engineering technique to facilitate the formation of submicrometer-
to micrometer-sized particles for improving therapeutic efficiency. This technique is beneficial for poorly water-soluble
In a typical process, a drug is dissolved in an organic solvent, which is immiscible with the nonsolvent of choice. Ultrasound
is applied to achieve a stable emulsion. Each emulsified droplet can be subjected to heat or mass-transfer effects to achieve
evaporation, cooling, or diffusion and bring about the required degree of supersaturation and crystal nucleation. The application
of ultrasound assists in the dispersion and stabilization of the drug particles in the nonsolvent.
The mechanism of particle formation can be seen as a sequential process governed by applied ultrasound. After emulsification,
the droplet size of the organic solution decreases because the organic solvent evaporates at high temperatures. Concurrently,
the drug concentration within the droplet increases with time. When the supersaturation of drugs in the shrinking droplet
is high enough, the drug, and sometimes the excipient, crystallizes.