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 60

complex and beyond the scope of this topic; however, there are comprehensive
reviews on the topic for readers interested in more detail [ 19 - 22 ].
In the context of aerosol formation, the use of large lactose carrier particles that
are an order of magnitude or more larger in physical diameter than the primary API-
containing particles is one way to avoid problems with cohesiveness of a formula-
tion, if it contained just the latter [ 23 ]. Alternatively, API-containing particles may
be made less cohesive by preprocessing [ 24 ] or forming them to have a nearly
spherical shape [ 25 ]. As a general rule, the formulators seek properties that opti-
mize the efficiency with which single aerosol particles are formed in the airflow
generated by the patient upon inhalation. The vast majority of DPIs currently on the
market are passive, in that they rely on the inspiratory effort of the patient to provide
the energy to de-aggregate and aerosolize the API-containing particles [ 26 ].
However, a few newer devices are considered “active,” in that powder dispersion is
accomplished by a suitable component of the inhaler, such as an electronic vibrator
or impeller. Whichever option is under consideration, ultimately the APSD of the
aerosol that is inhaled therefore depends upon a combination of the formulator's
ability to optimize the powder disaggregation process and the device developer's
ability to adjust DPI resistance to focus the available energy where it is needed.
In terms of making measurements of DPI aerosol APSDs, the compendia have stan-
dardized the process, whereby sampling a fixed 4 L volume of air from the inhaler
occurs at the designated flow rate, using a critical orifice at the flow adjustment
valve to achieve sonic flow, rather than simulating the profile of an individual inha-
lation [ 27 , 28 ]. Under these circumstances, small changes in APSD are likely to
originate as much from the result of the environmental conditions under which the
measurements are conducted (in particular high relative humidity that may affect
powder cohesiveness [ 29 ] and the presence or absence of electrostatic charge [ 30 ]),
as they are from the inhaler itself.

3.3.1.2 Pressurized Metered-Dose Inhalers

MDI-based aerosol formation is also closely linked to the physicochemical charac-
teristics of the formulation contained in the pressurized canister, in particular if the
API is in solution or suspension [ 31 ]. However, the presence of the liquid propellant
under pressure introduces the ability for these inhalers to self-deliver the aerosol to
the patient when actuated, as the result of flash evaporation that takes place upon
actuation as the metered dose of liquid is exposed to ambient pressure and tempera-
ture [ 32 ]. Device design factors, in particular the construction of the metering valve
and orifice, play an important role in determining the APSD of the aerosol that is
ultimately released [ 33 ] for the patient to inhale. The APSD that is measured by CI
during MDI testing can be influenced by the temperature and relative humidity of
the testing environment, especially at high temperatures and relative humidity levels
[ 34 ]. For example, Lange and Finlay observed APSD changes when making mea-
surements at temperatures above about 35°C with the relative humidity above about
95% [ 35 ]. They attributed their findings as being likely due to changes in the droplet