Drug Targeting Organ-Specific Strategies

3.10 In Vitro Particle Size Analysis and Deposition Measurements 79
trast, collection efficiency in vivo decreases with decreasing particle size (deposition mechanism)
to a minimum of 20% for particles with an aerodynamic diameter of 0.5 µm (e.g. [8]).
The classification by impactors into a small number of classes for the relevant particle sizes
(one to seven) may provide insufficient discrimination. For example, the theoretical cut-off
(with 50% collection efficiency) for the third stage of the multistage liquid impinger (MSLI)
is 3.1 µm at 60 l min –1 for particles with a true density of 1.5 g cm –3 . So, the fraction retained
from the fourth impactor stage plus filter is smaller than 3.1 µm. If the MMAD of this fraction
is 2 µm, deposition efficiency in the respiratory tract can be nearly 40%. If however, the
MMAD of this fraction is only 1 µm, the deposition efficiency is only about 20%, which is
twice as low. This difference cannot be judged from the cascade impactor result.
Usually, the inspiratory flow through impactors is an on–off function: a (solenoid) valve is
opened to allow suction at a pre-set flow rate through the inhalation device over a certain period.
Some recent guidelines prescribe a flow rate corresponding with 4 kPa pressure drop
for DPIs. Asking and Olsson derived a useful relationship for the effective cut-off diameters
for the different stages of the MSLI as function of the flow rate for the range between 30 and
100 l min –1 [123]. Impactors have relatively large volumes and high airflow resistances which
confine the range of adjustable PIFR and FIR. Probably the major drawback of cascade impactor
analysis is that the technique is extremely laborious and time consuming.
Laser diffraction is a fast alternative for analysis of the size distribution of particles in an
aerosol cloud.The theory of laser diffraction is well understood [124,125]) but this technique
requires special measures to test inhalation devices and to interpret the results correctly. One
of the major problems is that flow adjustment through the inhaler is not possible. Furthermore,
the presence of carrier particles from adhesive mixtures may disturb the measurement
of the fine drug particles and the size distribution obtained is of an unknown delivered mass
fraction of the dose.These practical problems and limitations have been solved by the design
of a new modular inhaler adapter for the Sympatec laser diffraction apparatus (Figure 3.6).
Preseparator
Fine particle collector
Figure 3.6. Schematic representation of a new inhaler adapter for laser diffraction characterization of
the aerosol cloud.