Pharmaceutical Aerosol

By

Muhammad Farhan Sohail

Definition
Pharmaceutical aerosols are dosage systems
containing one or more active ingredient which
upon actuation emit a fine dispersion of liquid / or
solid materials in a gaseous medium.

Classification
Space Sprays
These are used o provide an airborne mist.
These have Particle size is less than 50 m.
Contain 70-80% propellant
Examples are: Room disinfectants, room
deodorizers, space sprays, air fresheners etc.

Surface Sprays
Used to carry an active ingredient to a surface.
Larger particle size
Contain usually 30-70% propellant.
Examples are: Dermatological aerosols, Nonpharmaceutical aerosols e.g. cologne sprays etc.

Advantages
Removal of single dose without contamination
of the remaining contents of system.
Stability of contents with respect to O2, CO2,
moisture etc.
Ease of delivery with single push of button.
No chance of back flow.
No rubbing is required.
Medicaments can be easily spread over wide
area.
Convenience, speed and ease of application.

 Immediate local application and effect.

Controlled and uniform dosage produced by
metered valves.
Dispersion of pressurized powders is available.
No-contamination by micro-organisms even
when valve is opened for spray.
It is clean process, no need of washing after
operation.
Being opaque, aerosol container protects the
product from light contact irritations can be
minimized by aerosol systems

Disadvantages
High cost because container, valve,
propellants and filling methods are more
expensive than traditional packs.
Disposal of exhausted aerosol packs may be
difficult.
Protection from heat is necessary otherwise
bursting may occur.
Refrigeration effect of propellant may cause
problems.
Toxicity of propellant may cause problems.
It is necessary to test the formulation against
all parts of container.

Components of aerosols
Propellant
Container

Valve and actuator

Product concentrate

Propellant
It is responsible for developing the pressure with in
the container to push the product when the valve
is opened and in the form of atomization or foam
production.
COMPRESSED GASES
Insoluble gases e.g. Nitrogen, Argon.
Soluble gases e.g., CO2, Nitrous Oxide

LIQUIFIED GASES
Fluorinated Hydrocarbons e.g.
Trichloro, monoflouro methane
Dichloro, diflouro methane
Diflouro ethane
Dichloro tetraflouro ethane

Hydrocarbons e.g.
Propane
Butane
Pentane
Hexane

Propellant
For oral and inhalation
Fluorinated hydrocarbons
Dichlorodifluromethane (propellent 12)
Dichlorotetrafluromethane (propellent 114)

Topical preparation
Propane
Butane
Isobutane

Compound gases
Nitrogen
Carbon dioxide
Nitrous oxide

Working of Propellant
When the propellant is sealed with in the aerosol
container with product concentrate equilibrium is quickly
established b/w the portion of propellant which remains
liquefied and that which vaporizes.
Vapors occupy the upper portion of the aerosol container.
These vapors exert pressure in all directions i.e. against
the container wall, valve, product concentrate etc.
Upon actuation, this pressure forces the liquid phase up
in the dip tube and out of the valve into the atmosphere.
As the propellant meets the air, it evaporates, leaving the
product concentrate as airborne liquid droplets or dry
powders depending upon the formulation.
In the container equilibrium is regained.

Containers
They must withstand high pressure as high as 140 to 180
psig (pounds per sq. inch gauge) at 1300 F. Also they
must be nonreactive towards the content.
Metals

Tinplated
(a) Side-seam (three pieces)
(b) Two-piece or drawn
(c) Tin free steel
Aluminium
(a) Two-piece
(b) One-piece (extruded or drawn)
Stainless steel

Glass
1. Uncoated glass
2. Plastic coated glass

Plastic
Not recommended because of many disadvantages

Actuator
To ensure that aerosol product is delivered in the
proper and desired form.
Different types of actuators

Spray actuators
Foam actuators
Solid steam actuators
Special actuators

Valve Assembly
ACTUATOR is the button which is pressed by user to activate
valve assembly for the emission of product.

Spray actuators (orifice -0.016-0.040 inch)

Foam actuators (orifice -0.070-0.125 inch)
Solid stream actuators
Special actuators in order to accomplish a specific purpose
e.g. to deliver the product in throat, nose, vaginal tract etc.

MOUNTING CAP attaches the valve to the container,

GASKET prevents leakage of formulation,
SPRING holds the gasket in place and bounces back the actuator
after release of pressure,
HOUSING located below the mounting cap and links the dip
tube, stem and actuator,
STEM supports the actuator,
DIP TUBE extends from housing down into the product; it
brings the product up to the valve.

Metered Dose Inhaler

These are valves which allow specific amount of
product to come out and then stop automatically.
Such valves contain reservoir of specific volume
which on actuation empties all the contents present
in it on single push of actuator.
So the function of VALVE ASSEMBLY is to permit the
expulsion of contents of containers:
In desired form
At desired rate
In proper amount or dose

Formulation of pharmaceutical aerosols

Contains two essential components
Product concentrate
Propellant
Product concentrate
Product concentrate contains ingredients or mixture of active
ingredients and other such as solvents, antioxidants and
surfactants.

Propellant
May be single or blend of various propellants
Blends of propellant used in a pharmaceutical
formulation to achieve desired solubility characteristics or
various surfactants are mixed to give the proper HLB
value for emulsion system.
To give the desired vapor pressure, solubility & particle
size.

Types of System

Solution system
Water based system
Suspension or Dispersion systems
Foam systems

Aqueous stable foams

Nonaqueous stable foams
Quick-breaking foams
Thermal foams

Intranasal aerosols

Solution System
A large number of aerosols can be formulated in this manner.
This is known as two phase system, i.e. vapor and liquids
phase.
When the active ingredient is soluble in the propellant then
no other solvent is required.
Depending on the type of spray required the propellant may
consists dichlorodifluoromethane and butane (which produce
very fine particle).
The amount of propellant used may vary from 5% for foam, to
95% for inhalation.
These spray are useful for topical preparation since they tend
to coat the effected area with a film of active ingredients
Aerosols intended for inhalation or for local activity in the
respiratory system in the treatment of asthma may be
formulated.

Water Based System

Active ingredient is insoluble in propellant.

It is three phase system (Propellant/water/vapor.)
Most of the non-aqueous liquids are replaced with water
to solubilize the A.I.
It is an emulsion formulation (W/P)
Surfactants are used to increase mixing of two
components, in conc. 0.5 -> 2%.
Propellant concentration is 25-60%.
If propellant is heavier than water, it is present below
water layer, and dip tube must be out of propellant but in
water layer.
If propellant is lighter than water, it will be present above
aq. product concentrate and dip tube must be reaching
the bottom of container i.e deep in aq. phase

Dispersion System

A.I is insoluble in water and propellant then it is

dispersed in the form of suspension.
Particle size should be less than 5 micron.
Suspension and propellant should be moisture free.
It is three phase system e.g.
Propellant, solid(A.I), Vapour (Propellant)
For oral inhalations mostly, it's physical stability can be
increased by:
Decreasing particle size < 5micron
Decreasing moisture contents < 300ppm
Using suitable surfactant (HLB < 10)
Using suspending agent.
Adjusting density of propellant and/or suspension

Foam System
Propellant concentration 6-8%.
Consists of emulsion of propellant + water +
drug + Emulsifier.
Three phase system.
Rapid vaporization of the propellant from
formulation granules give rise to foam
formation.

Foam System

Aqueous stable foam:

The propellant may be about 10% v/v or 3-5% w/w.
As the amount of propellant increases stiffer and dryer foam is produced.
Lower propellant concentration yield wetter foam.
Non-aqueous stable foam:
Non aqueous stable foam may be formulated through the use of various
glycols such as polyethylene glycols which may be formulated as glycol,
emulsifying agent and hydrocarbon propellant.
The emulsifying agent found most effective from class of glycol esters.
Quick breaking foam:
In this system the propellant is in the external phase.
When dispensed, the product is emitted as foam which than collapses
into the liquids
This type of system is usually applicable for topical medication without
mechanical force to apply.
Thermal foam:
This foam was developed several years ago to produce warm foam for
shaving.But it has been obsoleted due to expensive and less effectiveness.

Compress Gas System

Propellant is in the form of compressed gas.
There is no reservoir system.
Compressed gas is always filled with greater
proportion.
Gases insoluble in product e.g. nitrogen expel
the product in the same form as in container.
Gases soluble in product e.g. CO2 expel the
product in the form of sprays & foams.

Pre Val System

This system is meant for when propellant and product
concentrate are incompatible and are required to be separated
from each other during storage.
This consists of an aluminum cartridge containing propellant and
aerosol valve fitted on container having product conc.
When actuator is depressed, propellant vaporizes, escape from
propellant chamber and this effect draws some product up via dip
tube. At this stage propellant and product are mixed.
This mixing of propellant and product results in dispensing of
product in the form of spray.
Another system (parallel to pre-val system utilizes "accordion
pleated" plastic bag which contains product, and propellant is
injected between this plastic bag and container.

Manufacturing of Aerosol
To prepare and package of pharmaceutical aerosols
special knowledge, skill and equipment are required.
These operations must be carried out under strict
supervision and adherence to ensure quality control.
Manufacturing (addition of propellant to concentrate)
is carried out as a part of the package process.
In addition to the equipment used for the compounding
of liquids, suspension, emulsion, cream and ointment,
specialize equipment capable of handling and
packaging material at relatively low temperature -40F
or under high pressure must be available.

Filling of Aerosols
PRESSURE FILLING
By pressure filling, the product concentrate is quantitatively
placed in aerosol container, the valve assembly is inserted and
crimped into place, and liquefied gas, under pressure is metered
into valve stem from a pressure burette.
The desired amount of propellant is allowed to enter the container
under its own vapor pressure. When the pressure in container
equals that in the burette, the propellant stops flowing. Additional
propellant may be added by increasing pressure in filling
apparatus through use of compressed air or nitrogen gas.
Pressure filling is used for most pharmaceutical aerosols.
It has two advantages over cold filling:
There is less danger of moisture contamination of product.
Less propellant is lost in this process.

Filling of Aerosols
COMPRESSED GAS FILLING
In this process of aerosol filling, concentrate is placed
in the container, the valve is crimped in place and air is
evacuated.
The filling head is inserted into the valve opening the
valve is depressed and gas is allowed to flow into the
container.
When the pressure within the container is equal to the
delivery pressure the gas stop flowing.
For those products in which the solubility of gas is
more carbon dioxide and nitrous oxide can be used.
To obtain maximum solubility it is shaken manually or
with mechanical shakers.

Filling of Aerosols

COLD FILLING
In the cold method, both product concentrate and propellant
must be cooled to -34.5 to -40 C.
This temperature is necessary to liquefy propellant gas.
The cooling system may be a mixture of dry ice and acetone or a
more elaborate refrigeration system.
After the chilled product concentrate has been quantitatively
metered into equally cold aerosol container, the liquefied gas is
added.
The heavy vapors of cold liquid propellant generally displace
the air in the container.
When sufficient propellant has been added, the valve assembly
is inserted and crimped into place.
Because of low temperature required, aqueous systems cannot
be filled by this process, since water turns to ice.

Large scale equipment

Concentrate filler
Valve placer
Purger and crimper
Pressure filler
Leak test tank

Concentrate Filling
This range from single stage single Hooper to
a large straight line multiple head filler or a
rotary type multiple head filler.
According to production these filler deliver
the constant amount of product in one or
more operations.
Normally a part of product is added at each
stage for accuracy

Purger And Vacuum Crimper

Aerosols are packaged both in glass and metal
containers each require their own type of
crimper.
Combination can and bottle capper can be used
for most laboratory procedures and operate
manually or air pressure.
Most crimper serve as dual functions, that is to
evacuate the air within the container to about 24
inches of mercury and then seal the valve in
place.
Single head crimper and multiple rotary unit
capable of vacuum crimping up to 120 cans per
minute are available.

Valve Placing
The valve is placed on the container manually or automatically.
High speed equipment are used to place valve automatically.
This orients the valve and place its position prior to crimping
position

Pressure Filling
These unit are capable of adding the propellant
either through the valve, stem ,body ,and dip tube
around the outside stem, or under the valve cup
before crimping.
The single or multiple stage unit arranged in
straight line or as rotary units.
To speed production a positive pressure is
maintained to force the liquids propellant into the
container.
Evacuation of air from the container crimping the
valve and addition of the propellant can be achieved
in basically one operation through the use of an
under the cap filler.

Leak test tank

This consist of large tank filled with water and
containing heating units ,and a magnetize chain
so that the cans or pucks for glass ,aluminum
and plastic container are carried through and
submerged into the water
The length of tank is that the temperature of
products before emerge should be 130F.
Each completed container filled for shipment
must be heated until contents reached a
minimum of 130F without evidence of leaking
,distortion or other defects.

Quality control for pharmaceutical

aerosols
Propellants
Valves, actuator and dip tubes
Testing procedure
Valve acceptance
Containers
Weight checking
Leak testing
Spray testing

QC Test for Aerosol

Propellant
All propellant are checked for their purity and
identification mentioned on specification sheet.
For identification GC is used
For Purity Moisture, Halogen, Non-Volatile Residue
Determination

QC Test for Aerosol

Actuator, valve and dip tube:
The object of this test is to determine magnitude of valve delivery & degree of uniformity
between individual valves. Standard test solutions were proposed to rule out variation in valve
delivery.

Testing Procedure:
Take 25 valves & place on containers,
Filled with specific test solution
Actuator with 0.020 inch orifice is attached.

Valve is actuated to fullest extent for 2 sec.

Repeat this for total 2 individual delivery from each 25 test units.
Valve delivery / actuation microliter = individual deliverywt in mg/ sp. Gr of test sol
Limits
54L or less is 15%, 55 to 200 L is 10%
acceptance criteria:
4 or more out of 50 are outside the limit, rejected
3 are outside, another 25 checked, lot is rejected if more than one is outside the limit.

QC Test for Aerosol

Container
Containers are examined for defects in lining. Q.C
aspects includes degree of conductivity of electric
current as measure of exposed metals. Glass containers
examined for Flaws.
Weight Checking
Weight checking is done by periodically adding tarred
empty aerosol container to filling lines which after
filling with concentrate are removed & weighed. Same
procedure is used for checking weight of Propellants.

QC Test for Aerosol

Leak Test
Leak test is done by measuring the Crimps
dimension & comparing. Final testing of valve
closure is done by passing filled containers
through water bath.
Spray Testing
It is done for , To clear dip tube of pure
propellant & concentrate and To check for
defects in valves & spray pattern.

QC Test for Aerosol

Vapor pressure
Determined by pressure gauge. Variation in pressure indicates
the presence of air in headspace. A can punctuating device is
available for accurately measuring vapor pressure.
Density
It is Determined
by
hydrometer or a pycnometer. This
method is use for non aerosol, modification to accommodate
liquefied gas preparation. In which A pressure tube is fitted
with metal fingers and hoke valve, which allow for the
introduction of liquids under pressure. The hydrometer is
placed in to the glass pressure tube. Sufficient sample is
introduced through the valve to cause the hydrometer to rise
half way up the length of the tube. The density can be read
directly.

QC Test for Aerosol

Flame Projection
This test indicates the effect of an aerosol formulation on the
extension of an open flame.
Product is sprayed for 4 sec. into flame. Depending on the
nature of formulation, the fame is extended, and exact length
was measured with ruler.
Flash point
Determined by using standard Tag Open Cap Apparatus. In
which Aerosol product is chilled to temperature of - 25 0 F
and transferred to the test apparatus. Temperature of test
liquid increased slowly, and the temperature at which the
vapors ignite is taken a flash point. It is calculated for
flammable component, which in case of topical formulations is
hydrocarbons

QC Test for Aerosol

Moisture content
Karl Fischer method or Gas chromatography method has
also been used.
Aerosol valve discharge rate
It is determined by taking an aerosol known weight and
discharging the contents for
given time using standard
apparatus. By reweighing the container after time limit has
expired, the change in weight per time dispensed is discharge
rate.it is expressed as gram per seconds.

QC Test for Aerosol

Dosage with metered valves
Reproducibility of dosage each time the valve is
dispersed. Amount of medication actually received by the
patient. Reproducibility has been determined by assay
technique. Another method is that,
involves accurate
weighing of filled container fallowed by dispersing of several
doses, container can reweighed, and difference in weight
divided by No. of dose, gives the average dosage.
Net contents
Weight method.
Filled full container, and dispensing the contents.
Foam stability
Visual evaluation. Time for a given mass to penetrate the
foam. Times for given rod that is inserted into the foam to fall.
The use of rotational viscometers.

QC Test for Aerosol

Therapeutic Activity
For Inhalation Aerosols: is depends on the particle
size.
For Topical Aerosols: is applied to test areas &
adsorption of therapeutic ingredient is determined.
Toxicity
For Inhalation Aerosols: exposing test animals to
vapor sprayed from Aerosol container.
For Topical Aerosols: Irritation & Chilling effects are
determined.

Evaluation parameters of pharmaceutical aerosols

A. Flammability and combustibility
1. Flash point
2. Flame extension, including flashback
B. Physiochemical characteristics
1. Vapor pressure
2. Density
3. Moisture content
4. Identification of propellant(s)
5. Concentrate-propellant ratio
C. Performance
1. Aerosol valve discharge rate
2. Spray pattern
3. Dosage with metered valves
4. Net contents
5. Foam stability
6. Particle size determination
7. Leakage
D. Biologic characteristics
E. Therapeutic activity

REFERENCES
Bellis, Mary The History of Aerosol Spray Cans
Norwegian Patent No. 46613, issued on November 23, 1926

U.S. Patent Method and Means for the Atomizing or Distribution of Liquid or Semiliquid Materials, issued April
7, 1931
Kvilesj, Svend Ole (17 February 2003). "Sprayboksens far er norsk". Aftenposten (in Norwegian). Retrieved 6
February 2009.
Appratus for Mixing a Liquid With a Gas, granted August 22, 1939.

Carlisle, Rodney (2004). Scientific American Inventions and Discoveries, p.402. John Wiley & Songs, Inc., New
Jersey. ISBN 0-471-24410-4.
7, filed October 3, 1941 and granted October 5, 1943
Kimberley A. McGrath (Editor), Bridget E. Travers (Editor). World of Invention "Summary". Detroit: Thomson
Gale. ISBN 0-7876-2759-3.

Core, Jim, Rosalie Marion Bliss, and Alfredo Flores. (September 2005) "ARS Partners With Defense Department To
Protect Troops From Insect Vectors".Agricultural Research MagazineVol. 53, No. 9 .

Valve Mechanism for Dispensing Gases and Liquids Under Pressure; application September 28, 1949, issued
March 17, 1953

"42T revolutionises aerosol production process". Business Weekly, 3 Feb 2011. page 16. Also [1]. Checked 11 Feb
2011.^ "Deodorant burns on the increase". ABC News. 10 July 2007.
Wikimedia Commons has media related to: Spray cansCAPCO (www.aerosolproducts.org) is a nonprofit
organization dedicated to providing accurate information about aerosol products
The Aerosol Products Division (www.aboutaerosols.com) of the Consumer Specialty Products Association also gives
facts and relevant information about aerosol products

Aerosol Spray Can Old Patents and Inventions

Thank you