Pharmaceutical Manufacturing Handbook: Production and

5.8.6.2
Size Reduction and Particle Formation Technologies
DRY POWDER INHALERS 701
Dry powder inhaler formulations consist usually of either a drug - only formulation
or an ordered mixture of drug and excipient, most commonly lactose monohydrate.
In both cases, the fi rst challenge is the production of drug particles with suitable
size characteristics for inhalation (i.e., 1 – 5 μ m). Traditionally, micronization or jet -
milling methods have been employed as the method of choice for conventional
small molecules. This method is identical to that employed for the production of
fi ne particles for suspension MDIs. Using this method it is possible to produce
primary particles between 1 – 5 μ m. However, as a consequence of the particle size
reduction there are a number of undesirable effects with respect to the powder
properties. Micronized powders possess high intramolecular forces and are cohesive.
They readily form aggregates that are diffi cult to disperse to the primary particles.
Dispersion to its primary particle is essential for successful pulmonary deposition.
In addition, they often possess high inherent electrostatic charges which cause particle
adhesion to the components of the dry powder inhaler [169] . The high - energy
micronization process also causes disruption of the crystal lattice and results in the
formation of amorphous regions which may affect the long - term stability of the
formulation [170] . Finally, it is not possible to control the drug particle morphology.
Despite all of these problems, micronization remains the most common technique
employed for respirable particle formation. Modifi cations to conventional micronization
techniques have been investigated as alternative methods of particle size
reduction [171 – 173] .
A number of novel particle formation technologies now exist that are able to
produce respirable drug particles for formulation in both DPIs and MDIs. Depending
on the method of preparation, these particles offer unique and potentially
advantageous physical and aerodynamic properties compared to conventional crystallization
and micronization techniques. Some investigators have advocated that
major improvements in aerosol particle performance may be achieved by lowering
particle density and increasing particle size, as large, porous particles display less
tendency to agglomerate than (conventional) small and nonporous particles. Also,
large, porous particles inhaled into the lungs can potentially release therapeutic
substances for long periods of time by escaping phagocytic clearance from the lung
periphery, thus enabling therapeutic action for periods ranging from hours to many
days [174] .
Many of these techniques involve particle formation from solution formulations
that contain novel excipients. Spray drying is the most advanced of these technologies
and has been used to produce the powder formulation in the Exubera inhaler
[175] . Various modifi cations of this basic technique, including co – spray drying with
novel excipients, have been employed.
AIR particles are low - density lipid - based particles that are produced by spray
drying lipid – albumin – drug solutions. These particles are characterized by their
porous surface characteristics and large geometric diameter while having a low
aerodynamic diameter [176, 177] . This technology has been used to produce porous
particle powder formulations of L - dopa that have been investigated for the treatment
of Parkinson ’ s disease [178] .
Pulmospheres are produced using a proprietary spray drying technique, with
phosphatidylcholine as an excipient to produce hollow and porous particles with