Pharmaceutical aerosols

Question 1

What is an aerosol?

Answer 1

Any system of solid or liquid particles of sufficiently small diameter to maintain some stability as a suspension in air

Question 2

What factors affect aerosol deposition? (3)

Answer 2

1. Physical properties of the aerosol particle
2. Ventilation factors
3. Regional airway anatomy/lung mechanics

Question 3

What are the Physical properties of Aerosols (3)

Answer 3

1. Particle size
2. Particle shape and density
3. Aerodynamic diameter

Question 4

Particle size: why are smaller particles better

Answer 4

Smaller particles achieve:
greater total lung deposition
farther distal airways penetration and more peripheral (edge) lung deposition compared with larger particles

Question 5

What effect does Particle shape and density have

Answer 5

Spherical particles: particle size = particle diameter
* Non-spherical particles: particle size influenced by
shape and density
* Therefore, the term “diameter” is not strictly applicable
* Use the term aerodynamic diameter instead

Question 6

Aerodynamic diameter

Answer 6

• Definition: The diameter of a unit density sphere with the same settling velocity as the particle in question

Question 7

Aerodynamic diameter equation

Answer 7

dpa = dps √pp
where: dpa is the aerodynamic diameter,
dps is the Stokes diameter of the particle pp is particle density

Question 8

Stokes diameter

Answer 8

• The Stokes diameter for a particle is the diameter of a sphere that has the same density
  and settling velocity as the particle
• For smooth, spherical particles, the Stokes diameter is identical to the physical or actual diameter

Question 9

Mass Median Diameter (MMD or xg)

Answer 9

MMD is the particle diameter that divides the frequency distribution in half:
* 50% of the aerosol mass has particles with a larger diameter
* 50% of the aerosol mass has particles with a smaller diameter

Question 10

Geometric Standard Deviation (σg)

Answer 10

Describes how spread out the values are in the log-normal distribution
* For a log-normal distribution, 68% of particles have a diameter between
xg/sg andxg x sg
* Always greater than or equal to 1.0
* For a pure monodisperse aerosol population (narrow size distribution)
sg = 1.0
* For a polydisperse aerosol population (wider size distribution) sg ≥ 1.25

Question 11

Mass median aerodynamic diameter (MMAD)

Answer 11

Definition: Aerodynamic diameter around which the mass is centred.
* Both shape and density are accounted for
* Therefore, 50% of the particles by weight will be smaller than the MMAD, 50% will be larger
* Important parameter used in clinical studies that describe the deposition of particles in the respiratory tract

Question 12

What are the various mechanisms of deposition?

Answer 12

• Inertial impaction
• Gravitational sedimentation
• Brownian diffusion
• Electrostatic precipitation

Question 13

Inertial Impaction

Answer 13

Particles that tend to continue in their present trajectory rather than follow the curvature of the airways i.e. impact the airway wall
* Mechanism dominant in the oropharynx and major bronchi for rapidly inhaled particles >5 μm
* To impact a surface, the particles must have enough inertial momentum to overcome the drag force of the gas flow on the particles
* The probability of impaction is equal to: Ud²sin𝞱/R

Question 14

Ud²sin𝞱/R what does each part mean

Answer 14

velocity x diameter² x sin angle of airway turn
————
radius

Question 15

Gravitational Sedimentation

Answer 15

smaller particles that are able to follow the airstream and penetrate the more peripheral bronchioles and alveoli (airstream flows slower here)
Depends on the terminal velocity of a particle under the influence of gravity
Terminal velocity of a particle increases proportionally to its density and square of its diameter
It is enhanced by breath-holding or slow, steady breathing
Particles <2 μm deposit in the lower airways by gravitational sedimentation

Question 16

Brownian diffusion

Answer 16

Brownian diffusion an important mechanism for particles <0.5 μm in diameter
Small particles are displaced by the random bombardment of gas molecules and collide with the airway walls
*These very small aerosols deposit in the distal lung
This mechanism does not account for the deposition of therapeutic
aerosols where the practical sizes are ~1–10 μm

Question 17

Electrostatic Precipitation

Answer 17

The charge on an aerosol can enhance the deposition of very small aerosols that have a high mobility (not as important for aerosols that are larger than 4 µm in diameter)
May cause problems when aerosol delivery systems are composed of plastics that carry a high charge
Also important when plastic spacers are used with pressurised metered dose inhalers

Question 18

2. Ventilation Factors

Answer 18

Particle velocity

Inspiratory flow

Inspired volume

Breath-hold duration

Timing of aerosol delivery during inspiration

Question 19

Particle velocity

Answer 19

Determined by the aerosol generator

The basic function of an aerosol generator is to generate a drug-containing aerosol cloud that contains the highest possible fraction of particles in the desired size range

Pressurised metered-dose inhaler particle velocities range from 10-100 m/s

Current dry powder and jet/ultrasonic nebulisers have low velocities

Question 20

Inspiratory flow

Answer 20

Typical inspiratory flows during quiet tidal breathing ~ 0.25-0.5 L/s

Faster inspiratory flows increase oropharyngeal and upper airway deposition by inertial impaction

Slower inspiratory flows minimise oropharyngeal and upper airway deposition and enhance distal delivery through gravitational sedimentation

Question 21

What does the Size of inspired volume affect

Answer 21

Amount of aerosol that enters the lung

Depth of penetration of the aerosol into the lung

Question 22

Breath-holding

Answer 22

Enhances deposition by facilitating gravitational sedimentation

Breath-holding for at least 4 sec important

Breath-holding is important for smaller particle sizes as they have an increased chance of being exhaled because they can remain airborne for a considerable time

Question 23

Timing of aerosol administration

Answer 23

Delivery of the aerosol early in inspiration puts the aerosol at the “front end” of the breath for deeper penetration

Delivery of the aerosol later in inspiration puts the aerosol at the “back end” for delivery to later-filling lung units

Question 24

3. Airway anatomy/lung mechanics

Answer 24

Affects regional delivery
Lung regions with poor ventilation due to air flow obstruction will receive a lower volume of delivered aerosol
Sharp branching airways or mucus accumulation will enhance proximal airway deposition through inertial impaction and reduce more distal aerosol delivery in that region
However, slower regional flows may reduce delivery but actually enhance deposition due to gravitational sedimentation