Current Approaches to APSD Measurements of OIPs Based on Inertial Impaction - Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products - page 17

number (Kn p ) in which the size of the particle in terms of d p is related to the mean
free path length of a molecule of the surrounding air ( λ ), where [ 1 ]

Kn p = 2 l / d (2.4)

p

and

( )

C c =+ 105 . Kn 2 34 . + 105 . xp − 0 195 . Kn (2.5)

p p

The value of C c asymptotically approaches unity for particle sizes larger than a
few micrometers and can generally be ignored unless the mass-weighted APSD
(either differential or cumulative plot of API mass versus d ae [ 1 ]) contains an appre-
ciable proportion of particles < 0.5 μm.
The multistage CI links the determination of mass of API in the OIP aerosol with
d ae and has been therefore accepted by both the compendial [ 4 , 5 ] and regulatory [ 6 , 7 ]
authorities as the apparatus of choice for sizing these aerosols. Alternative aerody-
namic particle size characterization techniques, such as particle time of flight (TOF)
in accelerating motion, can size aerosols based on the d ae scale more rapidly than the
CI method [ 8 ]. However, such near real-time methods do not, at the present time,
provide traceability to the mass of API(s) in the formulation through the use of well-
defined and widely accepted analytical assay principles (i.e., high-performance liquid
chromatography combined with a quantitative spectroscopic detection method,
usually UV/visible light absorption or fluorescence that is API specific) [ 9 ]. This
latter attribute is regarded as being of critical importance by the major regulatory
agencies [ 6 , 7 ]. The foci of this chapter, and the topic as a whole, are therefore on
OIP aerosol particle sizing by CI-based methods.

2.2 The CI Is Not an In Vitro Analog of the Human

Respiratory Tract

It has often, but erroneously, been promoted that multistage CI-derived APSD data
can directly indicate the fate of the particles in the human respiratory tract (Fig. 2.2 ).
If this situation was totally true, such data would be ideal for estimating the like-
lihood of clinical response in studies of the efficacy and safety of OIPs. However, it
is important at the outset to realize that the CI is fundamentally not a lung simulator,
as more mechanisms governing particle deposition are at play in the HRT. The dif-
ference between the two becomes readily apparent when overlaying the collection
efficiency curves of the ACI, chosen as a representative multistage CI, with the cor-
responding empirical/theoretical particle collection efficiency curves associated
with the morphological regions within the respiratory tract (Fig. 2.3 ).
The relatively poor size selectivity of the HRT has been recognized for many
years by the community of aerosol scientists involved with environmental pro-
tection [ 11 ], where three subfractions covering inhalable particles are currently