The power of ultrasound
Sonocrystallization, or ultrasound-assisted crystallization, relies on the power-ultrasound (20–100 kHz) and extended-sonochemistry
(100 kHz–2 MHz) bands of the acoustic-frequency range. By comparison, human hearing responds to frequencies between 20 Hz
and 19 kHz.
Ultrasound involves mechanical vibrations that transfer energy by molecular motion. One consequence of ultrasound vibration
is cavitation, the transient high-energy microbubbles formed when power ultrasound is applied to a liquid medium. The energy
release associated with this phenomenon, once dissipated, can lead to permanent changes in the molecular structure of entities
in close proximity.
Conversely, ultrasound can be used in various medical applications, diagnostic pulse-echo techniques, attenuation measurements,
and particle separation, without any change to the medium or species suspended or dissolved in the liquid medium.
The acoustic bubble
The advantages that sonocrystallization offers over conventional crystallization largely result from cavitation. The microbubbles
caused by cavitation are short-lived microreactors where responses and reactions such as chemical reaction and crystal nucleation
take place in a uniquely favorable environment as large amounts of energy are transferred to reagent molecules in an extremely
short time (6, 7).
Most ultrasound work has used either intense-probe or ultrasonic-bath-based equipment. Although cavitation is the essential
element for successful sonocrystallization, including ultrasonic wet milling, it can be harmful to an ultrasound-radiating
surface. Cavitation usually damages the ultrasonic device and creates problems with ultrasonic probes, where cavitation occurs
close to the radiating surface. These engineering limitations can be overcome, however.
Small particles and sonocrystallization
Sonocrystallization can be applied at any stage of pharmaceutical manufacturing and lends itself to polymorphic systems (7,
8). The technique uses transient acoustic cavitation to assist in the nucleation of metastable solutions. By controlling nucleation,
one controls and improves crystal-size distribution, morphology, impurities, polymorphism, and solid–liquid separation. Ultrasound
can also induce secondary nucleation by mechanically disrupting crystals or loosely bound agglomerates.
Companies such as Prosonix, GlaxoSmithKline (Brentford, UK), AstraZeneca (London), and Syngenta (Basel) have patented crystallization
methods based on ultrasound-assisted precipitation, principally for the preparation of nano- and microcrystalline particles
(9–13). The cavitation-induced effects can be so strong that nanosuspensions can be prepared when the antisolvent is water.
Molecule-to-particle techniques using power ultrasound such as antisolvent precipitation take advantage of the excellent dispersive
and crystal-nucleation properties of transient cavitation. Several companies that manufacture microparticles and nanosuspensions
are adopting these techniques. Precipitation conditions must be chosen to maximize crystal nucleation at the expense of growth,
which will necessitate having the appropriate prevailing supersaturation.
Rabinow gives a useful overview of the preparation, delivery, and performance of nanosuspenions, but in simple terms, a solution
of the API must be added to the antisolvent (water) at an optimal rate to generate micrometer- and, where necessary, submicrometer-sized
particles (3). One problem with this strategy is that supersaturation can force a phase separation and lead to oiling or rapid
precipitation of amorphous forms and metastable polymorphs, because of slow nucleation kinetics. Yet more stable solid forms
can eventually form, as indicated by Ostwald's law of stages. How does power ultrasound help?
Acoustic cavitation can have remarkable benefits for the system of interest, whether it is the manufacture of microparticles
or nanosuspensions. Cavitation not only improves mixing and increases the diffusion of molecules toward a precrystal cluster
or nucleus, it facilitates the formation of a crystalline phase (14). This latter effect is attributed to dramatic temperature
and pressure changes, shockwaves, and rapid local cooling rates (15).
The continuous mixing of a solution of API in a suitable miscible solvent with an antisolvent, whether water or an organic
solvent, in a flow cell fitted with an ultrasonic probe shows the potential of the sonoprecipitation and sonocrytallization
of microcrystalline pharmaceutical products (11). During the course of the process, the solvent–antisolvent ratio always remains
constant, and flow rates must be balanced. Nevertheless, this continuous technique has potential advantages.
Water-insoluble drug substances can be dissolved in a water-miscible organic solvent that can then be added to water in the
presence of an ultrasonic field. The ultrasound can be applied using an immersed ultrasonic probe to generate a dispersion.
The form of the dispersion depends upon ultrasonic energy and the presence or absence of stabilizers (12). Even though acoustic
cavitation occurs during the initial mixing, amorphous particles are produced. Amorphous particles are considered essential
for avoiding crystal growth if crystalline phases are present. Applying continuous ultrasound after mixing leads to the formation
of crystalline submicrometer-sized particles through a solution-mediated amorphous-to-crystalline transition.
If it is important to avoid organic solvents and the organic compound of interest has a suitably low melting point, sonocrystallization
can aid antisolvent crystallization in several ways. Sonocrystallization typically helps through a process that disperses
the melted liquid into the antisolvent water, solidifies the melted droplets, and subsequently or concurrently crystallizes
the compound (13). The ability to apply any particle-engineering methodology or technology on an industrial scale is paramount.