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 56

quality decision-making process. There are several textbooks available that address
the fundamentals of the various aerosol generation processes, and the reader is
referred to these for more detailed information [ 1 - 5 ]. Although somewhat older
than the other texts, the topic edited by Morén et al. is particularly signiicant
because it addresses how inhaler aerosols interact with the respiratory tract in the
context of the diagnosis and treatment of lung diseases.
The creation of aerosols containing medication for inhalation in general involves
one of the following basic processes [ 6 ]:
(a) Rapid flash evaporation of a metered dose of formulation containing the API(s)
in either a high-volatile hydrofluoroalkane (HFA) or an older similarly high-
volatile chlorofluorohydrocarbon (CFC) propellant by means of a metered-dose
inhaler (MDI).
(b) Dispersion of a dry powder containing the API(s); in so-called passive DPIs,
dispersion takes place by the energy associated with the vacuum created during
inhalation, and in the newer so-called active systems, the energy comes from an
external source.
(c) Atomization of bulk liquid containing the API(s) by various means, including
the mechanical breakup of liquid forced through one or more fine orifices (soft
mist inhalers—SMIs), the expansion of air from a narrow orifice entraining the
liquid stream by the Bernoulli principle (jet nebulizer), the application of ultra-
sonic energy (ultrasonic nebulizer), the electromechanical vibration of one or
more orifices or capillaries (vibrating mesh/membrane nebulizer), and the
application of high electrostatic charge to the liquid stream (electro-spray), all
of which create instability in the emanating liquid stream(s).
(d) A few inhalers (currently in development) make use of controlled evaporation
of a low-volatile liquid containing the thermally stable medication by means of
an integral heat source, followed by condensation as the vapor moves away
from the heat source to exit the inhaler.
There are thus many variants associated with each form of inhaler. As well as
hand-operated MDIs, where the patient has to take care of coordinating inhaler
actuation, in recent years there has been increasing interest in the development of
breath-actuated MDIs [ 7 ] because such devices avoid the coordination issue alto-
gether. Nebulizers, by virtue of their external gas source (either from a fixed com-
pressed gas supply or portable compressor), also avoid the need for patient
coordination, although breath-enhanced and breath-actuated devices provide
improved drug output during patient inspiration [ 8 ]. Alternatively, tube spacers and
VHCs have been developed as add-on devices for MDIs during the past 30 years to
assist patients using MDIs, as they also eliminate the need for perfect coordination
with inhaler actuation [ 9 ]. Passive DPIs, by virtue of the fact that they make use of
the inspiratory effort from the patient to create the aerosol, ensure coordination, but
their effective delivery of medication may be impeded if the energy transfer to the
dry powder is reduced because the user cannot generate sufficient effort [ 10 ].
However, relatively high-resistance DPIs have been shown to provide better medi-
cation delivery to the lower respiratory tract than do lower resistance devices [ 10 ].