Two mechanisms allow the crystal nuclei to form larger drug particles: the drug molecules in the organic phase diffuse toward
the nuclei and condense, and the nuclei collide and coagulate together to form larger particles (16). At this stage, applied
ultrasound plays a significant role in controlling the size of resulting particles. Although the particles can grow, predominantly
by coagulation, ultrasound helps to deagglomerate and form submicrometer-sized crystalline particles. At high supersaturation,
or a low particle-growth rate, submicrometer-sized particles can be produced. Because the concentration of the organic solvent
in nonsolvent is extremely low, the particle growth through Ostwald ripening may be expected to be low relative to precipitation
In all these dispersive crystallization methods, many parameters can influence particle characteristics and require optimization.
They include ultrasonic power, concentration and feed rate of API solution, and temperature and flow rate of antisolvent.
For emulsion crystallization, particle size is also governed by the interplay between dispersion, coagulation, deagglomeration,
supersaturation, and Ostwald ripening (16, 17). The suspensions may be dried by common means such as supercritical carbon-dioxide
extraction, spray drying, lyophilization, and centrifugation. Small-scale automated equipment can be used for designed studies
to facilitate scale-up to the pilot plant.
Aerosolization, sonocrystallization, and SAX
Particle-engineering technology, especially techniques that control the production of microcrystalline particles with a narrow
size distribution and overcome the disadvantages of common micronization techniques, has shown great promise in preparing
particulate pharmaceuticals with defined physicochemical properties.
Techniques for producing drug particles include spray-drying, which involves generating an aerosol of droplets from a solution
of the drug and subsequent drying of the droplets to solidify the particles. Spray-drying is one of the most widely used industrial
processes involving particle formation and drying. It is highly suited for the continuous production of dry solids in either
powder, granulate, or agglomerate form from, for example, liquid feedstocks such as solutions, emulsions, and suspensions.
The end product of the spray-drying process should comply with quality standards for parameters such as particle-size distribution,
residual moisture content, bulk density, and particle shape. A disadvantage of conventional spray-drying techniques is that
the particles produced tend to be amorphous—perhaps as much as 100%—rather than in a crystalline particulate form because
solidification is typically rapid.
Newer techniques offer greater control of crystallinity and morphology. To achieve optimal drug delivery to the lung, it is
important to ensure that the drug is formulated into particles of the appropriate aerodynamic size, shape, and density.
Prosonix developed the SAX technology for preparing micro- and nanocrystalline particles for drug delivery and now seeks to
industrialize the process. These particles are used principally for inhaled medicines for asthma and COPD as well as antibiotics
(18). SAX and other sonocrystallization technologies could change the manufacturing of inhaled medicines significantly.
Multiple therapeutic areas
SAX is a scalable, economic technology that generally functions at ambient temperature and pressure (19–21). This solution-to-particle
methodology avoids many of the problems apparent with the various methods available to date. Importantly, SAX also allows
the production of spherical drug particles with unique nanotopology and superior aerodynamic properties. These characteristics
improve the sorption characteristics by virtue of the increased particle surface area for a given size and volume.
SAX has been applied to many compounds to date, including new chemical entities (NCEs) and many steroidal compounds for asthma,
COPD, and topical creams and gels. SAX has been used to prepare budesonide, fluticasone propionate, beclamethasone dipropionate,
ciclesonide, betamethasone and mometasone furoate, -agonists for asthma and COPD, salmeterol xinafoate, formoterol fumarate,
and salbutamol. Prosonix has also used SAX successfully for producing aminoglycoside and cephalosporin antibiotics.