Industrial Pharmacy, Chapter 6, Pharma Aerosols

Introduction
¾ They are pressurized dosage forms that upon actuation emit a fine dispersion of liquid
/solid material/ in a gaseous medium.
¾ They different from other dosage forms in their dependence upon
o the functioning of the container
o Its Valve
o The propellant
¾ Pressure is applied to the aerosol system through the use of one of move liquefied or
gaseous propellant.
¾ Upon actuation of the valve assembly of the aerosol, the pressure exerted by the
propellant forces the contents of the package out through the valve
¾ The contents of an aerosol may be
o A fine mist
o A coarse wet
o Dry spray
o A steady steam
o A stable fast breaking foam
¾ Inhalations contain a fine mist
o Particles less than 6µm will reach the respiratory bronchioles s
o Those less than 2 µm will reach the alveolar ducts and the alveoli
- For dermal use coarse sprays are used
6.1. Advantage of the aerosol Dosage forms
1. A portion of medication may be easily withdrawn from the package without
contamination.
2. Protect the medicine from environmental insults
3. For topical preparation, uniform thin layer to the skin is maintained without touching the
affected area.
- Irritation is decreased which may happen by mechanical application of topical
medications.
6.2. The Aerosol Principle
An aerosol formulation consists of two component parts,
1. The product concentrate and
2. The propellant
” Product concentrate may which may contains
- API
- Adjuncts
” Propellant:- The propellant is responsible for developing the proper pressure with the
container, and it expels the product when the value is opened and aids in the atomization or
foam production of that product.
- When the propellant is a liquefied gas or a mixture if liquefied gases, it frequently serves
the dual role of propellant and solvent or vehicle for the product concentrate

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Industrial Pharmacy, Chapter 6, Pharma Aerosols
” Chlorofluoro carbon CFC’s are being phased out for many aerosol systems, however,
pharmaceutical aerosols are still using CFC’s
Pharmaceutical aerosols are wavered from CFCS regulation because of the following reasons
1. There are no technically feasible alternatives
2. The products provides essential health service
3. The use does not involve significant release of CFS
Note: CFS louses depletion of the ozone layer
Egs of pharmaceutical Aerosols
o Dichloro difluoromethane
o Dichloro tetra fluoroethane
” Fluorinated HC’s are gases at room TO. They may be liquefied by cooling below their
boiling point or by compressing at room TO
Principle
When a liquefied gas propellant or propellant mixture is sealed with an aerosol container with in
the product, equilibrium is quickly established between the portion of the propellant that remain
liquefied and that which vaporized and occupies the upper portion of the aerosol container.
The vapor phase exerts pressure in all directions against.
- The wall
- The valve assembly
- The surface of the liquid phase
” It is this pressure that upon actuation of the aerosol valves forces liquid phase up the dip tube
and out of the orifices of the valve into the atmosphere
The pressure of an aerosol is critical to its performance
It can be controlled by
a. The type and amount of propellant e.g. surface aerosols 30-70%and foam=10%
b. The nature and amt of the concentrate
Foam Aerosols
- They are emulsions, the product is emulsified with the product concentrate
- The use of surfactants encourages the mixing of the aqueous (drug) and the non-aqueous
HC Propellants.
- Shacking of the package prior to use further mixes the propellant.
6.4Aerosol Systems
1. Two-Phase systems
Consists of

• the liquid phase Which are the liquefied propellant and the drug concentrates
• The vapor phase
2. Three phase system

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Industrial Pharmacy, Chapter 6, Pharma Aerosols
Consists of
1. A layer of highly aqueous product concentrate
2. A layer of water immiscible liquid propellant
3. The vapor phase
3. Compressed Gas systems
- Compressed gases rather than liquefied gases may be used to prepare aerosols
- The pressure of the compressed gas in the head space of the aerosol container forces the
product concentrate up the dip tube and out of the value.
” N2 gas usually employed
” Unlike aerosols prepared with liquefied gas propellant, compressed gas filled aerosols have
no reservoir of propellant. Thus higher gas pressure is required in these systems and the
pressure in these aerosols diminishes as the product is being used.
6.5Aerosol container and valve Assembly
Aerosol container
a. glass (uncoated or plastic coated)
b. Metals
” tin plated steel
” Al
” Stainless steel are used
c. Plastics
” The selection of the container depends on
9 production adaptability
9 Product compatibility
9 Ability to sustain pressure
9 Aesthetic appeal
9 Cost
Valve Assembly
Should permit expulsion of the content
9 In desired form
9 At desired rate
9 In the proper amt

Valve materials
- Plastics stainless steel
- Rubber
- Al
Components of Aerosols valve
1) Actuator – The button the user presses to activate the value assembly for emission of the
product.

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Industrial Pharmacy, Chapter 6, Pharma Aerosols
The design of the inner chamber and size of the emission orifices of the actuator
fcontributes to the physical form.
9 Mist - Solid Steam
9 Coarse spray - Foam
Larger orifices land less propellant are used for products to be emitted as foam and solid steams
than for those intended to be sprays or mists.
2) Stem – supports the actuator and delivers the formulation in proper form to the chamber
of the actuator.
3) Gasket- prevents leakage of the formulation when the valve is closed.
4) Spring- retracts the actuator for when pressure is released, returning the valve to the
closed position.
5) Mounting cup- holds the valve in place
6) Housing-links the dip tube and the other actuator
7) Dip tube- Brings the formulation from the container to the valve

6.6Metered dose inhalers

- The amount of material discharged is regulated by an auxiliary valve chamber by the
virtue of its capacity of dimension.
- A single depression of actuator causes evacuation of this chamber and delivery of its
content.
6.7Manufacturing of Pharmaceutical Aerosols
Filling Operation
CFC `s may be liquefied by cooling below their boiling point or by compressing the gas at room
TO.These two features are used in filling of aerosol propellant to containers.
- Therefore, specialized equipments capable of handling and packaging materials at low to
or under high pressure must be available.
1. Pressure filling Apparatus

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Industrial Pharmacy, Chapter 6, Pharma Aerosols
Consists of:

• Pressure burettes capable of metering small volume of liquefied gas under

pressure into an aerosol container.
• The desired amount of propellant is allowed to flow through the aerosol
value into the container under its own upper pressure.
2. Cold filling
Both the product concentrate and the propellant must be cooled to - 34.50 to-400c.
The cooling system may be dry ice and acetone.
- After the chilled product concentrate has been quantitively meted into an equally cold
aerosol, container, the liquefied gas is added.
- The Heavy vapor pressure of the cold liquid propellant displaces the air in the container.
- Finally the valve assembly is inserted and crimped.
- Aqueous systems are not filled by this process, since the water turns to ice
6.8 Large scale equipments
1) Concentrate filler
This can be – single stage fillers
- Large straight line filler
- Rotary filler
2) Valve placer
- This is done prior to crimping
3) Purge and vacuum crimperer
Most crimpers serve a dual function
- Evacuate the air with in the container
- Seal the values in place
Single to 120 cans/min crimpers are available.
Pressure fillers – These units are capable of adding the propellant either through
ƒ The valve stem
ƒ The body
ƒ the dip tube
ƒ Under the valve cup before crimping.
Leak test tank
This consists of a large tank filled with water and containing heating units and a magnetized
chain so that the cans/ puck for glass or metal parts of plastics are submerged into the water.

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Industrial Pharmacy, Chapter 6, Pharma Aerosols
Each container filled for shipment must have been heated until contents reached a min of 540c
without evidence of leaking distortion or other defeats.
6.9Manufacturing procedure
Production takes place in two stages
1) Manufacture of concentrate
2) Addition of propellant
- For this reason, part of the mfg operation takes place during the filling operation, which
is different from non aerosol pharmaceutical products
N.B the type of product and the size of container usually influence the type of filling to be
used .
Cold filling is restricted to non aqueous products and to those products not adversely affected
by low temperature
For the most part, the pressure system is preferred because some solutions, emulsions,
suspensions and others cannot be chilled.
Advantages of Pressure filling method
1) Less danger of contamination of produce with moisture
2) High production speed
3) Less propellant is lost
4) The method is not limited

6.10Quality Control for Pharmaceutical Aerosols

1) Propellants
- Test for its vapor pressure
- Test for its destiny
- When blends of propellants are used test for identity using Gas chromatography
2) Valves, Actuators and Dip tubes
Valves:-

- The magnitude of the valves delivery

- The degree of uniformity between individual doses
” A test solution is prepared with different specific gravity.
- Then a valve is selected and placed into a suitable container which contains the test solution
- The product is kept at 250c and the container is weighed.
- The valve is actuated to the fullest extent for at least 2 sec to province a complete dispensing of a
single dose
- Repeat this procedure 10 x and reweight the product
- The difference between the weights represents the delivery in mg.

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Industrial Pharmacy, Chapter 6, Pharma Aerosols
- The individual delivery weights in mg are divided by the specific gravity of the test solution to
obtain the value delivery per actuation in µlit
Valve acceptance
For valves delivering
54 µlit or less, + 15%,55 to 200 µlit, + 10%
Containers
- Defects in the lining
- Degree of conductivity
- Test for dimensions
- The weight of the bottle,
Leak testing:- by passing container in a water bath
Spray testing:-
- All pharma Aerosols are 100% tested for spray
The reasons for this are;
” To clear the dip tube of pure concentrate
” To check for defects in the valve and spray pattern
Other tests
A. Flammability & combustibility
1. Flash point
2. Flaw extension
B. Physicochemical characters
1. vapor pressure
2. Density
3. Moisture content
4. identification of propellants
5. Concentrate propellant ratio
C. Performance
1. Aerosol value discharge rate
2. Spray pattern
3. Dosage with metered values
4. Net contents
5. From stability
6. Particle size determination
7. Leakage
D. Biologic characters

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Industrial Pharmacy, Chapter 6, Pharma Aerosols
Test methods
1 flammability and combustibility testes
The flammability and combustibility of an aerosol is determined by
a) Flame projection
- Indicates the effect of an aerosol on the extension of on open flame.
- The product is sprayed for about 4 sec into a flame.
- The flam is extended and exact length being measured with a ruler.
b) Flash point
The aerosol product is chilled -310c and the liquid is allowed to increase slowly in To, and the To
at which the vapor ignite is taken as the flash point.
2. Vapor pressure test
- Using a pressure gauge
3. Density
- Using the hydrometer or a picnometer
4. Moisture
¾ Using the karl Fisher method
¾ Using GC
5. Identification of propellant
- Using a GC or IR Spectrophotometer.
6. Foam stability
The life of foam can range from a few sec to ones hr or more, depending on the formulation,
7. Particle size determination
- Using light scattering method
8. Biologic test
- Like the efficiency of preservatives/ preservative challenge test
9. Toxicity test
- Degree of irritation when applied to the affected area in the case of topical aerosols
- Inhalation toxicity for topical aerosol, accomplished by exposing test animals to vapors
spray from aerosol containers.

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