Physical Causes of APSD Changes in Aerosols from OIPs and Their Impact on CI Measurements - Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products - page 62

liquid against a mesh or membrane containing a multitude of similar-sized orifices
[ 39 - 42 ].
The pneumatic atomization process generally produces bimodal droplet distri-
butions [ 43 , 44 ]. Baffles and other obstructions are therefore located close to the
orifice(s) through which the liquid stream emerges as the result of the Bernoulli
effect, when the driving gas pressure is applied to operate the nebulizer. The aero-
sol available for inhalation therefore comprises a higher proportion of fine drop-
lets <5 m d ae than would be the case for unrestricted atomization of a liquid

stream [ 45 ]. The electronics associated with ultrasonic, SMI, and vibrating mesh/
membrane nebulizers can be adjusted so that the aerosol is predominantly of fine
droplets [ 40 ].
The measurement of APSD for nebulized suspension formulations is compli-
cated by the fact that the relative size of the API particles to the droplets of nebu-
lized liquid influences the measurement [ 46 ]. For example, a shift to finer droplet
sizes caused by either a variation in critical components associated with the nebu-
lizer itself, or more likely, an increase in driving gas pressure, will likely result in
less efficient incorporation of the API particles, especially if their size is commen-
surate with the liquid droplets.
Solution formulations by definition are a homogeneous dispersion of the API, so
that the resulting droplet APSDs determined by cascade impactor reflect only the
operating conditions of the nebulizer (i.e., driving gas pressure and flow rate for
pneumatic systems, vibration frequency for vibrating mesh/membrane systems, liq-
uid pressure for SMIs), together with the local environment into which the aerosol
is dispersed. In particular, control of relative humidity is important, particularly
when the nebulized aerosol is not surrounded by saturated gas, as is the case with jet
nebulizers without air entrainment that creates a locally saturated environment [ 47 ].
A further concern when evaluating nebulizing systems is the transfer of heat
from the cascade impactor to the droplets, enhancing their evaporation, and thereby
resulting in bias to finer sizes [ 48 ]. For this reason, the new normative chapter in the
European Pharmacopoeia concerned with nebulizer testing recommends that the
impactor be chilled [ 49 , 50 ].

μ

3.3.2 Aerosol Transport and APSD

Once the OIP aerosol has been created, there are several processes that affect its
APSD during transport to either the CI or to the patient. These aerosols are in a
continuous process of change as the relative motion of the individual particles com-
bines them (agglomeration), inertial forces associated with their movement relative
the flow streamlines of the surrounding support gas removes them by impaction
onto adjacent surfaces (inertial/turbulent deposition), or the influence of gravity
deposits them (gravitational sedimentation). The presence of electrostatic charge
either intrinsic to the aerosol or present on adjacent nonconducting surfaces can also
have a major effect on the APSD that gets measured.