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 69

3.3.2.6 Evaporation and Condensation Processes

Whenever there is either a volatile species (e.g., water, ethanol) present, or the
presence of hygroscopic solid particles, consideration needs to be given to the
effects of either evaporation or condensation (primarily from environmental mois-
ture) upon the APSD of the OIP aerosol being measured. Generally, the flash evapo-
ration of HFA or CFC propellants takes place rapidly on MDI actuation [ 72 ]. This
process is largely complete by the time that the resulting aerosol has stabilized by
eliminating the initial ballistic motion through drag on the individual particles by
the surrounding gas molecules. From this time onwards, the particles retain the local
gas velocity associated with inhalation or being sampled by the CI. Orifice design
characteristics, specifically expansion orifice diameter, orifice jet length and expan-
sion chamber sump depth, have been shown to be important in determining aerosol
plume development associated with the propellant evaporation process [ 73 ].
However, these dimensions are fixed in early-stage product development, so that
APSD changes originating from a manufactured inhaler design are likely to be
small. However, if the atomized droplets contain a low-volatile cosolvent for the
API, most usually ethanol, the process of evaporation to form the residual particles
may take several seconds [ 74 ], so that the measurement process can be challenging
to obtain reproducible results [ 34 ]. Unfortunately, the compendia currently do not
provide guidance on how to compensate for incomplete cosolvent evaporation, and
it is therefore likely that the process will not be complete until the aerosol has passed
through the initial stages of the CI [ 74 ].
The evaporation of aqueous droplets formed from nebulizing systems has already
been discussed in connection with the aerosol formation process (Sect. 3.3.1.3 ). The
process can be extremely rapid, especially under dry conditions [ 53 , 75 ], taking
place within a few tens of milliseconds. The time scale for evaporation can be
appreciated by referring to the data on time-dependent droplet diameter reduction at
15 L/min and 30 L/min, in which the ambient RH was 40%, presented in Fig. 3.4 .
Put in perspective, the time taken for an aerosol to pass through the 85 mL Ph. Eur./
USP induction port [ 76 ] at 15 L/min and 30 L/min, assuming plug flow, would be of
the order of 0.34 s and 0.17 s, respectively.
Droplet evaporation kinetics are strongly related to the initial droplet formation
process, as well as the local relative humidity of the surrounding gas [ 53 ]. The
example of droplet evaporation kinetics associated with sampling from a vibrating
mesh nebulizer [initial droplet diameter ( d ini ) = 4.3

m, liquid feed rate ( Q l ) = 0.296
ml/min], by an NGI at two different flow rates at room ambient conditions ( T amb and
RH amb of 21°C and 40%, respectively) as shown in Fig. 3.4 , is helpful to understand
the time scale of the evaporation process. However, it should not be seen as being
more than an illustration of the scenario that can be anticipated under subsaturated
conditions. Droplet evaporation is suppressed when the surrounding air is saturated
( RH amb = 100%), and this may be closer to conditions in the human oropharynx
( RH op ca. 75%) for oral breathing [ 77 ], than room ambient relative humidity values
that are typically <50%. However, there are practical limitations to working under

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