Pharmaceutical Aerosols

May Saab
Associate Professor
Pharmaceutical Technology Department
Faculty of Pharmacy, BAU
 Pharmaceutical Aerosols

➢ Definition
➢ Advantages
➢ Components
➢ Pressurized Metered Dose Inhalers (PMDIs)
➢ Deposition of inhaled drug particles
➢ Manufacturing processes of PMDIs
➢ Quality control tests of PMDIs

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 Pharmaceutical Aerosols

➢ Pharmaceutical aerosols are systems that depend on the

power of a compressed or liquified gas to expel the drug from
the container in form of stream, mist or foam.

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 Advantages of Pharmaceutical Aerosols

➢ Stability
➢ Sterility
➢ Direct delivery to the affected area
➢ Ease of application in a thin layer

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 Components of Aerosol Product

➢ Propellants
➢ Drug
➢ Surfactants
➢ Cosolvents
➢ Container
➢ Valve and Actuator

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 Propellants

➢ Propellants should be:

• Non toxic
• Stable
• Compatible with other components
• Exert sufficient pressure

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 Types of Propellants

➢ Liquified Gas:
• CFC (e.g. trichloromonofluoromethane or freon 11,
dichlorodifluoromethane or freon 12, dichlorotetrafluoroethane or
freon 114)
• HFA (e.g. tetrafluoroethane HFA-134a and heptafluoropropane HFA-
227)
• Hydrocarbons (e.g. Butane, propane)
➢ Compressed gas:
• N2 and CO2

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 Liquified Propellant

➢ The vapor pressure is constant and

independent on the quantity of the
liquified gas
 Compressed Gas

➢ The pressure decreases

➢ Spray characteristics change

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 Surfactants
➢ Surfactants are mixed with propellants to act as a suspending
agent and to lubricate the valves (concentration 0.1-2 % w/w)
➢ Examples of commonly used surfactants: sorbitan esters,
oleic acid and lecithin.
 Cosolvents
➢ Surfactants are poorly solubilized in HFA propellants, which
necessitate the addition of a co-solvent.
➢ Co-solvent most commonly used is ethanol
 Containers

➢ Metal:
• Stainless steel
• Aluminum (most widely used)
➢ Glass
• uncoated glass
• Plastic coated glass

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 Valve and Actuator

➢ Easily opened and closed

➢ Seal the container hermetically
➢ Regulate the passage of the product from the container
➢ Deliver the product in the desired form

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Valve and Actuator

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 Valve and Actuator

➢ When the actuator is pressed,

the dip tube path is opened to
the outside and large pressure
differential is created.
➢ The system wants to move to
equilibrium, and so the
product is forced through the
dip tube and out the actuator,
where the atomizer finely
disperses the product into an
aerosol spray.

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 Types of Actuators

➢ Spray Actuator:
• Small orifice that allow the passage of spray
(propellant > 50%)
➢ Foam Actuator:
• large chamber so the product can expand and
pass through a large orifice
➢ Solid stream:
• With large orifice for semi solid products
(ointment)
➢ Special applications

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 Special Application Actuators

➢ Designed to deliver the drug to the appropriate site of action:

• Nose
• Throat
• Lungs

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 Pressurized metered dose inhaler
➢ This type of inhalers has a
metered valve that delivers an
accurate volume each time the
valve is actuated
➢ It is used in the inverted position
➢ Depression of the valve stem
allows the contents of the
metering chamber to be
discharged through the orifice in
the valve stem and made
available to the patient

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 Pressurized metered dose inhaler
➢ After actuation, the metering chamber refills with liquid from
the bulk and is ready to dispense the next dose
➢ It needs to be primed

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 Deposition of inhaled drug particles

➢ For most drugs administered by inhalation, the desired site of

action lie deep in the respiratory tract in the bronchioles and
alveoli
➢ Inhalers usually deliver the drug in the form of aerosol droplets
having a certain aerodynamic diameter
 Aerodynamic Diameter

➢ It is the diameter of the perfect sphere that would fall through

air at the same speed as the aerosol particle
➢ Aerodynamic diameter > 5-10 μm particles deposit in
the upper regions of the respiratory tract
➢ Aerodynamic diameter 1-5 μm particles are capable of
reaching the bronchioles and alveoli
 Deposition Mechanisms

Particles may be deposited on the mucosa of the respiratory

tract in one of three ways:
1. Inertial impaction
2. Sedimentation
3. Diffusion
 1. Inertial Impaction

➢ Particles that possess high momentum cannot change

direction easily and tend to collide immediately with the walls
of the respiratory tract
➢ It provides an efficient mechanism for the removal of large,
fast moving particles in the upper parts of the respiratory
tract.
 2. Sedimentation

➢ Sedimentation of particles is influenced by gravity and

particles settle at a rate dependent on its aerodynamic
diameter
➢ In the upper airways, however, settling may be retarded by
the force of air
➢ In the lower airways the velocity of airflow may be insufficient
to maintain a particle in suspension, which will deposit by
gravitational forces
➢ Particles size (1-5µm)
 3. Diffusion

➢ Particles below 0.5 µm diameter display Brownian motion and

move from area of high to low particle concentration
➢ Particles leave the airstream (aerosol cloud) and deposit on
the walls of the respiratory tract
➢ The rate of diffusion increases with decreasing particle size
 Factors influencing particle deposition

1. Particle size
2. Breathing patterns:
• The larger the inhaled volume, the greater the peripheral distribution
of particles in the lung
• Breath-holding after inhalation enhances the deposition of particles
by sedimentation and diffusion
 Manufacturing Processes
➢ Cold Filling
➢ Pressure Filling

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 Cold filling Process

➢ Propellants are liquified by cooling at - 35

to - 40 °C
➢ A mixture of chilled propellant and
product concentrate are added in the
container
➢ The valve is then crimped in place
➢ Not used for hydrocarbons (explosive)
➢ Not used for formulations affected by low
temperature
➢ Not used for aqueous preparations

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 Pressure filling Process

➢ The concentrate is added at room

temperature and the valve is crimped in
place.
➢ The liquified propellant (under high
pressure) is added in the container
through the valve stem
➢ More preferred (more stability, less
explosion hazards, Less moisture
contamination)

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 Quality Control Tests
(Package)
➢ Valves:
• Determine the magnitude of the valve delivery and the degree of
uniformity between the individual valves of any given lot of metered
aerosol valves.
• Valve is actuated and the test unit is reweighed, and the difference
between it and the previous weight represents the delivery.
• The test procedure is repeated for a total of two individual deliveries
from each of 25 test units.

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 Quality Control Tests
(Package)
➢ Containers:
• Checked for defects
➢ Spray test:
• Check for defects in valves
➢ Leak test:
• Aerosol package are placed in a water bath at around 50 °C and
checked for defects, distortion or leakage.

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 Quality Control Tests
(Package)
➢ Valves:
• For 54 μL or less, the limits are ± 15%.
• For 55 to 200 μL, the limits are ± 10%.
• Of the 50 individual deliveries, if four or more are outside the limits for
the specified valve delivery, the valves are rejected.
• If three individual deliveries are outside the limits, another 25 valves
are sampled, and the test is repeated. The lot is rejected if more than
one delivery is outside the specifications.

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 Quality Control Tests
(Aerosol)
➢ Propellant Identity and purity:
• Gas chromatography
➢ Net content:
• Empty and filled containers are weighed and difference is calculated.

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 Quality Control Tests
(Aerosol)
➢ Particle Size Distribution
• A Cascade impactor is
commonly used that operates
on the principle of spraying
the aerosols into the device
such that the particles are
projected through a series of
nozzles and collection plates at
high velocity
• The larger particles become
impacted first, and the smaller
particles pass on and are
collected at the next stages.

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