SAX provides the platform for a particle-engineering solution whereby a single droplet containing the two APIs in an exact
ratio can be converted to a combination particle that contains the same drug substances as separate crystalline entities.
In combination therapies for asthma and COPD, where particle engineering is essential to formulation, the APIs often have
synergistic action at the molecular and cellular levels (e.g., inhaled steroids and long-acting agonists) and must be delivered
in an exact ratio (22).
The particles of both ingredients should have a high degree of crystallinity. Importantly, they must arrive at the site of
action in the lung together. Triple therapy, using an anticholinergic as the third component, is possible with SAX combination-particle
technology. The preparation of such combination particles could also have a significant part to play in areas of cancer chemotherapy,
where multiple drugs are prescribed.
The principles of SAX are simple (see Figure 3). SAX involves the formation of a drug-substance solution followed by its atomization,
controlled evaporation of the solvent, collection of the preconcentrated viscous droplets in a vessel containing nonsolvent,
and crystallization through nucleation with power ultrasound. The product slurry is then transferred to solid isolation, preferably
by spray-drying or supercritical carbon-dioxide drying.
Figure 3 (ALL IMAGES ARE COURTESY OF PROSONIX.)
SAX has developed considerably since its inception and is now available for full-scale demonstration, proof-of-concept studies,
and establishing the proof of process for scale-up studies. The technique provides opportunities to evaluate engineered particles
for their superior performance in terms of therapeutic efficiency and long-term stability. SAX technology could potentially
be the platform to improve the manufacture of superior particles for existing drug moieties, substances, and NCEs in development.
Figure 3 shows photographs of the SAX technology for research and development.
Solvent and solubility
Many parameters can influence particle characteristics and require optimization. The concentration of the solute in the solution
has considerable influence on the particle size and the volume of the drug particulate. The particle size and the volume tend
to increase as the concentration of solute in solution increases. The main reason for this is the increase in the relative
abundance of solute in the atomized solution compared to that of a dilute solution. The solute concentration should be optimized
by considering the desired particle size and the process economics. As a rule of thumb, the drug that is selected for the
process should exhibit optimum solubility in the selected solvent. The interaction of the drug with the selected solvent or
nonsolvent should be given due consideration to discover the possibility of solvate generation, which may be undesirable in
Atomizer and atomization
The choice of atomizer and its operation govern the particle size of the drug. The atomizer employed in the process should
efficiently atomize the drug solution to microdroplets so that they evaporate and contract to yield microcrystalline particles.
Good control of gas pressure can help in the size distribution of resulting particles (see Figure 4). The increase in gas
pressure can lead to smaller droplet size, which in turn yields a smaller particle following evaporation and concentration
of the droplet. Submicrometer-sized particles are routinely obtained through careful selection of pressure conditions employed
with the desired atomizer. The two-fluid nozzle performs better and is ideally suited to scale-up. It is important to optimize
the gas pressure and flow rate to achieve the best atomization and evaporation characteristics.
Figure 4 (ALL IMAGES ARE COURTESY OF PROSONIX.)
Depending on the choice of solvent, the gas pressure and flow rates are adjusted to achieve a uniform temperature profile
along the length of the column. For a given compound and ideal choice of dissolution solvent, it is imperative to achieve
an ideal and almost precise temperature profile along the length of column at a given solution feed rate and corresponding